WO2015058661A1 - Bcr-abl激酶抑制剂及其应用 - Google Patents

Bcr-abl激酶抑制剂及其应用 Download PDF

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WO2015058661A1
WO2015058661A1 PCT/CN2014/088911 CN2014088911W WO2015058661A1 WO 2015058661 A1 WO2015058661 A1 WO 2015058661A1 CN 2014088911 W CN2014088911 W CN 2014088911W WO 2015058661 A1 WO2015058661 A1 WO 2015058661A1
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alkyl
group
hydrogen
halogen
compound
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PCT/CN2014/088911
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English (en)
French (fr)
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王勇
赵立文
刘阳
张景忠
王德忠
高毅平
陈宏雁
张仓
张迪
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南京圣和药业股份有限公司
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4995—Pyrazines or piperazines forming part of bridged ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

  • the present invention belongs to the field of chemical medicine, and in particular relates to a compound having BCR-ABL kinase inhibitory activity or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, and a pharmaceutical composition containing the same The use of these compounds or compositions in the preparation of pharmaceuticals.
  • Protein tyrosine kinases are a class of kinases that catalyze the transfer of gamma-phosphate on ATP to protein tyrosine residues, which are initiated by catalyzing the phosphorylation of phenolic hydroxyl groups on various protein tyrosine residues.
  • a proteinase system that functions as a functional protein.
  • Protein tyrosine kinases (PTKs) play an important role in the signal transduction pathways in cells, regulating a series of physiological and biochemical processes such as cell growth, differentiation and death. Abnormal expression of protein tyrosine kinase can lead to disturbances in cell proliferation regulation, which in turn leads to tumorigenesis.
  • Tyrosine kinase inhibitors act as competitive inhibitors of adenosine triphosphate (ATP) binding to tyrosine kinases, competitively bind to tyrosine kinases, block tyrosine kinase activity, and inhibit cell proliferation.
  • ATP adenosine triphosphate
  • tyrosines already exist. Acid protein kinase inhibitors have been successfully developed.
  • CML chronic myeloid leukemia
  • the long arm of chromosome 22 translocates to chromosome 9, forming a Philadelphia chromosome, and leads to the fusion of BCR gene and ABL gene to form a BCR-ABL fusion gene, expressing BCR-ABL protein tyrosine kinase.
  • BCR-ABL is not expressed in normal cells and has become an ideal drug target for the treatment of CML.
  • BCR-ABL tyrosine kinase inhibitors have become the first-line treatment for most chronic myeloid leukemias.
  • Imatinib is the first protein-targeted therapeutic protein tyrosine kinase inhibitor that inhibits BCR-ABL tyrosine kinase at the cellular level, selectively inhibits BCR-ABL-positive cell lines and Philadelphia Proliferation of fresh leukemia cells in chromosome-positive (Ph+) chronic myeloid leukemia (CML) and acute lymphoblastic leukemia (ALL) patients induces apoptosis.
  • Ph+ chromosome-positive
  • CML chronic myeloid leukemia
  • ALL acute lymphoblastic leukemia
  • the development and clinical use of imatinib has opened a new era of tumor molecular targeting, but long-term use of imatinib will produce drug resistance, leading to relapse. With the widespread clinical application of imatinib, the problem of drug resistance has become increasingly prominent.
  • imatinib resistance has ignited a wave of research and development of a new generation of tyrosine kinase inhibitors, in order to develop better CML, Ph+ for the treatment of leukemia, such as drug resistance or non-resistance. ALL's new drug.
  • Another object of the invention is to provide a process for the preparation of a compound of formula I of the invention, or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof.
  • a further object of the present invention is to provide a composition comprising a compound of Formula I of the present invention, or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, and a pharmaceutically acceptable carrier, and a composition comprising the same A composition of a compound of formula I or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof and another protein tyrosine kinase inhibitor.
  • a further object of the present invention is to provide a compound of the formula I according to the invention, or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, for treating and/or preventing a tumor, and the method of the invention Use of a compound of formula I or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof for the manufacture of a medicament for the treatment and/or prevention of a tumor.
  • the present invention provides a compound of formula I or a pharmaceutically acceptable salt, isomer, solvent thereof Compound, crystal or prodrug,
  • X is selected from N and C(R 5 ), wherein R 5 is selected from the group consisting of hydrogen, halogen, C 1-6 alkyl, halo C 1-6 alkyl;
  • Y is selected from N and C(R 6 ), wherein R 6 is selected from the group consisting of hydrogen, halogen, C 1-6 alkyl, halo C 1-6 alkyl;
  • R 1 is selected from the group consisting of hydrogen, alkyl, alkoxy, haloalkyl, haloalkoxy, -OH, -NH 2 , halogen, and CN;
  • R 2 is selected from the group consisting of hydrogen, alkyl, alkoxy, haloalkyl, haloalkoxy, -OH, -NH 2 , halogen, and CN;
  • W is selected from C 1-6 alkylene, -C(O)-, forms a 4-8 membered cycloalkyl group with R 4 or is absent;
  • R 3 is selected from substituted or unsubstituted five-, six-, seven- and eight-membered nitrogen-containing heterocyclic groups
  • R 4 is selected from hydrogen, alkyl, haloalkyl, or together with W to form a 4-8 membered cycloalkyl;
  • the compounds of the invention are compounds of formula I, and pharmaceutically acceptable salts, isomers, solvates, crystals or prodrugs thereof, wherein:
  • X is selected from N and C(R 5 ), wherein R 5 is selected from the group consisting of hydrogen, fluorine, chlorine, bromine, C 1-4 alkyl, halo C 1-4 alkyl;
  • Y is selected from N and C(R 6 ), wherein R 6 is selected from the group consisting of hydrogen, fluorine, chlorine, bromine, C 1-4 alkyl, halo C 1-4 alkyl;
  • R 1 is selected from the group consisting of hydrogen, C 1-4 alkyl, C 1-4 alkoxy, halo C 1-4 alkyl, halo C 1-4 alkoxy, -OH, -NH 2 , fluorine, chlorine , bromine and CN;
  • R 2 is selected from the group consisting of hydrogen, C 1-4 alkyl, C 1-4 alkoxy, halo C 1-4 alkyl, halo C 1-4 alkoxy, -OH, -NH 2 , fluorine, chlorine , bromine and CN;
  • W is selected from C 1-4 alkylene, -C(O)-, forms a 4-8 membered cycloalkyl group with R 4 or is absent;
  • R3 is selected from substituted or unsubstituted azacyclohexanes having 1, 2 or 3 nitrogen atoms selected from alkyl, hydroxy, hydroxyalkyl, alkoxy, amino, monoalkylamino, Dialkylamino, amido, An alkylamido group, an aryl amido group, a heteroaryl amido group, a halogen, a halogen-substituted alkyl group, a halogen-substituted alkoxy group, preferably the substituent is selected from a C1-6 alkyl group, a hydroxyl group, a hydroxy group C1- 6 alkyl, C1-6 alkoxy, amino, mono C1-6 alkylamino, bis C1-6 alkylamino, acylamino, C1-6 alkylamido, aryl amide, heteroaryl amide A halogen, a halogen-substituted C1-6 alkyl group, or a halogen-substitute
  • R 4 is selected from hydrogen, C 1-6 alkyl, halo C 1-6 alkyl or, together with W, a cyclopentyl group, a cyclobutane group, a cyclohexane group or a cycloheptyl group.
  • the compounds of the invention are compounds of formula I, and pharmaceutically acceptable salts, isomers, solvates, crystals or prodrugs thereof, wherein:
  • X is selected from N and C(R 5 ), wherein R 5 is selected from the group consisting of hydrogen, fluorine, chlorine, bromine, C 1-4 alkyl, halo C 1-4 alkyl;
  • Y is selected from N and C(R 6 ), wherein R 6 is selected from the group consisting of hydrogen, fluorine, chlorine, bromine, C 1-4 alkyl, halo C 1-4 alkyl;
  • R 1 is selected from the group consisting of hydrogen, C 1-4 alkyl, C 1-4 alkoxy, halo C 1-4 alkyl, halo C 1-4 alkoxy, -OH, -NH 2 , fluorine, chlorine , bromine and CN;
  • R 2 is selected from the group consisting of hydrogen, C 1-4 alkyl, C 1-4 alkoxy, halo C 1-4 alkyl, halo C 1-4 alkoxy, -OH, -NH 2 , fluorine, chlorine , bromine and CN;
  • W is selected from C 1-4 alkylene, -C(O)-, forms a 4-8 membered cycloalkyl group with R 4 or is absent;
  • R 3 is selected from pyridazinyl, pyridyl, azabicycloalkyl, imidazolyl, pyrazolyl, pyrrolyl, triazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, acridinyl, triazinyl, Or substituted pyridazinyl, pyridyl, azabicycloalkyl, imidazolyl, pyrazolyl, pyrrolyl, triazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, acridinyl, triazinyl, wherein The substitution is selected from the group consisting of alkyl, hydroxy, hydroxyalkyl, alkoxy, amino, monoalkylamino, bisalkylamino, acylamino, alkylamido, aryl amide, heteroaryl amide, halogen a halogen-
  • C 1-6 alkylamino bis C 1-6 alkylamino, acylamino, C 1-6 alkylamido, aryl amide, heteroaryl amide, halogen, halogen substituted C 1-6 alkane a halogen-substituted C 1-6 alkoxy group.
  • R 4 is selected from hydrogen, C 1-6 alkyl, halo C 1-6 alkyl or, together with W, a cyclopentyl group, a cyclobutane group, a cyclohexane group or a cycloheptyl group.
  • the compounds of the invention include a compound of formula I, and pharmaceutically acceptable salts, isomers, solvates, crystals or prodrugs thereof, wherein:
  • X is selected from N and C(R 5 ), wherein R 5 is selected from the group consisting of hydrogen, fluorine, chlorine, bromine, C 1-3 alkyl, halo C 1-3 alkyl;
  • Y is selected from N and C(R 6 ), wherein R 6 is selected from the group consisting of hydrogen, fluorine, chlorine, bromine, C 1-3 alkyl, halo C 1-3 alkyl;
  • R 1 is selected from the group consisting of hydrogen, C 1-3 alkyl, C 1-3 alkoxy, halo C 1-3 alkyl, halo C 1-3 alkoxy, -OH, -NH 2 , fluorine, chlorine , bromine and CN;
  • R 2 is selected from the group consisting of hydrogen, C 1-3 alkyl, C 1-3 alkoxy, halo C 1-3 alkyl, halo C 1-3 alkoxy, -OH, -NH 2 , fluorine, chlorine , bromine and CN;
  • W is selected from C 1-3 alkylene (eg, -CH 2 -, -CH 2 -CH 2 -), -C(O)-, and forms a cyclopentyl group with R 4 or is absent;
  • R 3 is selected from pyridazinyl, acridin-4-yl, diazabicyclooctylalkyl such as 3,8-diazabicyclo[3.2.1]octyl, said pyridazinyl, acridine- 4-Based, diazabicyclooctylalkyl may be substituted by one or more C 1-6 alkyl, C 1-6 alkoxy groups, for example by one or more methyl, ethyl, propyl, isopropyl Substituted by a base, a methoxy group, an ethoxy group or a propoxy group;
  • R 4 is selected from hydrogen, C 1-4 alkyl, halo C 1-4 alkyl, or together with W constitutes a cyclopentyl group.
  • R 6 is selected from the group consisting of hydrogen, halogen, C 1-6 alkyl, halo C 1-6 alkane
  • R 6 is selected from the group consisting of hydrogen, fluorine, chlorine, bromine, C 1-4 alkyl, halo C 1-4 alkyl, more preferably R 6 is selected from the group consisting of hydrogen, fluorine, chlorine, bromine, C 1- 3- alkyl, halo C 1-3 alkyl.
  • R 5 is selected from the group consisting of hydrogen, halogen, C 1-6 alkyl, halo C 1-6 alkane a group, preferably R 5 is selected from the group consisting of hydrogen, fluorine, chlorine, bromine, C 1-4 alkyl, halogenated C 1-4 alkyl, more preferably R 5 is selected from the group consisting of hydrogen, fluorine, chlorine, bromine, C 1- 3- alkyl, halo C 1-3 alkyl.
  • R 5 and R 6 are each independently selected from hydrogen, halogen, C 1-6
  • the invention provides a compound of formula Ia, or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof,
  • X is selected from N and C(R 5 ), wherein R 5 is selected from the group consisting of hydrogen, halogen, C 1-6 alkyl, halo C 1-6 alkyl;
  • Y is selected from N and C(R 6 ), wherein R 6 is selected from the group consisting of hydrogen, halogen, C 1-6 alkyl, halo C 1-6 alkyl;
  • R 1 is selected from the group consisting of hydrogen, alkyl, alkoxy, haloalkyl, haloalkoxy, -OH, -NH 2 , halogen, and CN;
  • R 2 is selected from the group consisting of hydrogen, alkyl, alkoxy, haloalkyl, haloalkoxy, -OH, -NH 2 , halogen, and CN;
  • W is selected from C 1-6 alkylene, -C(O)- or absent;
  • R 3 is selected from substituted or unsubstituted five-, six-, seven- and eight-membered nitrogen-containing heterocyclic groups, preferably R 3 is a substituted or unsubstituted azacyclohexane having 1, 2 or 3 nitrogen atoms Alkane, further preferably R 3 is pyridazinyl, pyridyl, azabicycloalkyl, imidazolyl, pyrazolyl, pyrrolyl, triazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, acridinyl, Triazinyl, or substituted pyridazinyl, pyridyl, azabicycloalkyl, imidazolyl, pyrazolyl, pyrrolyl, triazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, acridinyl, tri a pyridyl group
  • R 4 is selected from the group consisting of hydrogen, C 1-6 alkyl, halo C 1-6 alkyl;
  • the present invention provides a compound of Formula Ib, or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof,
  • X is selected from N and C(R 5 ), wherein R 5 is selected from the group consisting of hydrogen, halogen, C 1-6 alkyl, halo C 1-6 alkyl;
  • Y is selected from N and C(R 6 ), wherein R 6 is selected from the group consisting of hydrogen, halogen, C 1-6 alkyl, halo C 1-6 alkyl;
  • R 1 is selected from the group consisting of hydrogen, alkyl, alkoxy, haloalkyl, haloalkoxy, -OH, -NH 2 , halogen, and CN;
  • R 2 is selected from the group consisting of hydrogen, alkyl, alkoxy, haloalkyl, haloalkoxy, -OH, -NH 2 , halogen, and CN;
  • W is selected from C 1-6 alkylene, -C(O)- or absent;
  • R 3 is selected from substituted or unsubstituted five-, six-, seven- and eight-membered nitrogen-containing heterocyclic groups, preferably R 3 is a substituted or unsubstituted azacyclohexane having 1, 2 or 3 nitrogen atoms Alkane, further preferably R 3 is pyridazinyl, pyridyl, azabicycloalkyl, imidazolyl, pyrazolyl, pyrrolyl, triazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, acridinyl, Triazinyl, or substituted pyridazinyl, pyridyl, azabicycloalkyl, imidazolyl, pyrazolyl, pyrrolyl, triazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, acridinyl, tri a pyridyl group
  • R 4 is selected from the group consisting of hydrogen, C 1-6 alkyl, halo C 1-6 alkyl.
  • the invention provides a compound of formula Ic, or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof,
  • X is selected from N and C(R 5 ), wherein R 5 is selected from the group consisting of hydrogen, halogen, C 1-6 alkyl, halo C 1-6 alkyl;
  • Y is selected from N and C(R 6 ), wherein R 6 is selected from the group consisting of hydrogen, halogen, C 1-6 alkyl, halo C 1-6 alkyl;
  • R 1 is selected from the group consisting of hydrogen, alkyl, alkoxy, haloalkyl, haloalkoxy, -OH, -NH 2 , halogen, and CN;
  • R 2 is selected from the group consisting of hydrogen, alkyl, alkoxy, haloalkyl, haloalkoxy, -OH, -NH 2 , halogen, and CN;
  • R 3 is selected from substituted or unsubstituted five-, six-, seven- and eight-membered nitrogen-containing heterocyclic groups, preferably R 3 is a substituted or unsubstituted azacyclohexane having 1, 2 or 3 nitrogen atoms Alkane, further preferably R 3 is pyridazinyl, pyridyl, azabicycloalkyl, imidazolyl, pyrazolyl, pyrrolyl, triazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, acridinyl, Triazinyl, or substituted pyridazinyl, pyridyl, azabicycloalkyl, imidazolyl, pyrazolyl, pyrrolyl, triazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, acridinyl, tri a pyridyl group
  • the invention provides a compound of formula Id, or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof,
  • X is selected from N and C(R 5 ), wherein R 5 is selected from the group consisting of hydrogen, halogen, C 1-6 alkyl, halo C 1-6 alkyl;
  • Y is selected from N and C(R 6 ), wherein R 6 is selected from the group consisting of hydrogen, halogen, C 1-6 alkyl, halo C 1-6 alkyl;
  • R 1 is selected from the group consisting of hydrogen, alkyl, alkoxy, haloalkyl, haloalkoxy, -OH, -NH 2 , halogen, and CN;
  • R 2 is selected from the group consisting of hydrogen, alkyl, alkoxy, haloalkyl, haloalkoxy, -OH, -NH 2 , halogen, and CN;
  • R 3 is selected from substituted or unsubstituted five-, six-, seven- and eight-membered nitrogen-containing heterocyclic groups, preferably R 3 is a substituted or unsubstituted azacyclohexane having 1, 2 or 3 nitrogen atoms Alkane, further preferably R 3 is pyridazinyl, pyridyl, azabicycloalkyl, imidazolyl, pyrazolyl, pyrrolyl, triazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, acridinyl, Triazinyl, or substituted pyridazinyl, pyridyl, azabicycloalkyl, imidazolyl, pyrazolyl, pyrrolyl, triazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, acridinyl, tri a pyridyl group
  • R 1 is selected from the group consisting of hydrogen, alkyl, alkoxy, haloalkyl, halogen and CN, especially R 1 is selected from the group consisting of hydrogen, C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkyl, halogen, and CN.
  • R 2 is selected from the group consisting of hydrogen, alkyl, haloalkyl, halogen, and CN, particularly R 2 is selected from hydrogen. , C 1-6 alkyl, halo C 1-6 alkyl, halogen and CN.
  • R 3 is selected from the group consisting of 4-methylpyridazin-1-yl, acridin-4-yl, 1 -methyl acridin-4-yl, 3,8-diazabicyclo[3.2.1]octane-8-yl, 1-methyl-3,8-diazabicyclo[3.2.1]octane -8-based.
  • R 4 is selected from methyl and trifluoromethyl.
  • in Formulas I, Ia, Ib, Ic, Id, W and R 4 together form a cyclopentyl group.
  • R 5 is selected from hydrogen, halogen.
  • R 6 is selected from hydrogen, halogen.
  • R 1 is selected from the group consisting of hydrogen, methyl, trifluoromethyl, methoxy, ethoxy, C. Oxy or isopropoxy.
  • R 2 is selected from hydrogen, methyl, ethyl, propyl and isopropyl.
  • R 5 is selected from hydrogen, fluoro.
  • R 6 is selected from hydrogen, fluoro.
  • the present invention provides the following specific compounds:
  • the invention provides a process for the preparation of a compound of the formula of the invention.
  • the method for preparing a compound of formula I comprises the steps of:
  • R 1 , R 2 , R 3 , R 4 , W, X, Y have the meanings in the formula I, and M is selected from the group consisting of chlorine, bromine and iodine.
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of the invention, or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof.
  • the invention provides a compound of the invention, or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, and a compound comprising the same, or a pharmaceutically acceptable salt, isomer thereof
  • the invention provides a pharmaceutical composition comprising a compound, isomer, solvate, crystal or prodrug of the invention, further comprising one or more selected from the group consisting of a tyrosine protease Inhibitor, EGFR inhibitor, VEGFR inhibitor, BCR-ABL inhibitor, c-kit inhibitor, c-Met inhibitor, Raf inhibitor, MEK inhibitor, histone deacetylase inhibitor, VEGF antibody, EGF antibody , HIV protein kinase inhibitor, HMG-CoA reductase inhibitor, and the like.
  • a tyrosine protease Inhibitor EGFR inhibitor, VEGFR inhibitor, BCR-ABL inhibitor, c-kit inhibitor, c-Met inhibitor, Raf inhibitor, MEK inhibitor, histone deacetylase inhibitor, VEGF antibody, EGF antibody , HIV protein kinase inhibitor, HMG-CoA reductase inhibitor, and the like.
  • the compound, isomer, solvate, crystal or prodrug of the present invention may be mixed with a pharmaceutically acceptable carrier, diluent or excipient to prepare a pharmaceutical preparation suitable for oral or parenteral administration.
  • Methods of administration include, but are not limited to, intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, and oral routes.
  • the formulation may be administered by any route, for example by infusion or bolus injection, by a route of absorption through the epithelium or skin mucosa (e.g., oral mucosa or rectum, etc.). Administration can be systemic or topical.
  • orally administered preparations include solid or liquid dosage forms, specifically, tablets, pills, granules, powders, capsules, syrups, emulsions, suspensions and the like.
  • the formulations may be prepared by methods known in the art and comprise carriers, diluents or excipients conventionally employed in the field of pharmaceutical formulations.
  • the present invention provides a method, a method for treating and/or preventing a tumor of a compound, an isomer, a solvate, a crystal or a prodrug of the present invention or a pharmaceutical composition of the present invention, and in the preparation of a medicament for preventing and/or treating cancer
  • a compound, isomer, solvate, crystal or prodrug of the invention or a compound, isomer, solvate, crystal or prodrug of the invention to a tumor-prone population or tumor patient
  • the pharmaceutical composition is effective to reduce the incidence of tumors and prolong the life of tumor patients.
  • the invention provides methods for treating and/or preventing a tumor comprising administering to a subject in need thereof a therapeutically and/or prophylactically effective amount of a compound, isomer, solvate, crystal of the invention Or a prodrug or a pharmaceutical composition of the invention.
  • the compounds, isomers, solvates, crystals or prodrugs of the invention or pharmaceutical compositions of the invention may be administered to a mammal in need thereof to inhibit tumor growth, progression and/or metastasis, including solid tumors
  • tumor growth, progression and/or metastasis including solid tumors
  • solid tumors for example, breast cancer, colon cancer, gastric cancer, pancreatic cancer, central nervous system tumors, and head and neck cancers, as well as various forms of leukemia, including leukemia and other cancers that are resistant to other treatments such as imatinib or other kinase inhibitors,
  • the kinase is inhibited by a compound or composition of the invention.
  • alkyl group of the present invention means a linear, branched or cyclic saturated hydrocarbon group, preferably a C 1-6 alkyl group.
  • a suitable C 1-6 alkyl group includes, but is not limited to, a methyl group, a Base, n-propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, tert-butyl, cyclobutyl, n-pentyl, isopentyl, cyclopentyl, cyclohexyl, n-hexyl.
  • the alkyl group is further preferably a C 1-3 alkyl group, and a suitable C 1-3 alkyl group is a methyl group, an ethyl group, a propyl group, an isopropyl group, or a cyclopropyl group.
  • an alkyl group in the present invention includes a substituted or unsubstituted alkyl group, which may be optionally substituted with one or more groups selected from the group consisting of an alkyl group, an alkoxy group, an aryloxy group, Alkylamino, arylamino, halogen, hydroxy, amino, nitro, cyano, alkyl acyl, aminoacyl, alkylaminoacyl, sulfonyl, sulfinyl, decyl, aryl or heteroaryl.
  • alkoxy group of the present invention means an alkyl-O- group, preferably a C 1-6 alkyl-O- group, further preferably a C 1-3 alkyl-O- group, a suitable C 1-3 alkyl group - O- is methoxy, ethoxy, propoxy or isopropoxy.
  • halogen of the present invention means fluorine, chlorine, bromine or iodine, preferably fluorine or chlorine.
  • haloalkyl group of the present invention means an alkyl group substituted with at least one halogen, preferably a halogenated C 1-6 alkyl group, further preferably a halogenated C 1-3 alkyl group, a suitable halogenated C 1-3 alkane.
  • Base is chloromethyl, fluoromethyl, dichloromethyl, difluoromethyl, trichloromethyl, trifluoromethyl, chloroethyl, fluoroethyl, dichloroethyl, difluoroethyl, trichloro Ethyl, trifluoroethyl.
  • haloalkoxy group of the present invention means an alkoxy group substituted with at least one halogen, preferably a C 1-6 alkoxy group substituted with at least one halogen, and further preferably a halogenated C 1-3 alkoxy group, suitably Halogenated C 1-3 alkoxy is chloromethoxy, fluoromethoxy, dichloromethoxy, difluoromethoxy, trichloromethoxy, trifluoromethoxy; dichloroethoxy , difluoroethoxy, trichloroethoxy, trifluoroethoxy.
  • the "five-membered, six-membered, seven-membered, eight-membered nitrogen-containing heterocyclic group" of the present invention means that the substituted or unsubstituted has at least one ring, and the total number of ring atoms is five, six, seven, eight and A saturated, partially saturated, and fully unsaturated heterocyclic group containing at least one nitrogen atom.
  • the "five-membered, six-membered, seven-membered, eight-membered nitrogen-containing heterocyclic group” is pyridazinyl, pyridyl, azabicycloalkyl, imidazolyl, pyrazolyl, pyrrolyl, triazolyl , pyridazinyl, pyrimidinyl, pyrazinyl, acridinyl, triazinyl, or substituted pyridazinyl, pyridyl, azabicycloalkyl, imidazolyl, pyrazolyl, pyrrolyl, triazolyl, Pyridazinyl, pyrimidinyl, pyrazinyl, acridinyl, triazinyl, wherein said substituent is selected from the group consisting of alkyl, hydroxy, hydroxyalkyl, alkoxy, amino, monoalkylamino, bisalkylamino An
  • the "4-8 membered cycloalkyl group" of the present invention means a monocyclic or bicyclic saturated hydrocarbon group having 4 to 8 carbon atoms.
  • Suitable cycloalkyl groups include cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl and the like.
  • Other suitable cycloalkyl groups include spiropentyl, bicyclo[2.1.0]pentyl and bicyclo[3.1.0]hexyl, and the like.
  • Solvent refers to a solvent known or readily determinable by those skilled in the art. In the case of water, the solvate is generally referred to as a hydrate such as a monohydrate, a dihydrate, a trihydrate or the like.
  • Crystal as used in the present invention refers to various solid forms formed by the compounds of the present invention, including crystalline forms and amorphous forms.
  • “Isomers” of the invention include the compounds cis conformation, conformational isomer and enantiomer.
  • a conformational isomer refers to a cis-trans isomer of the cis or trans configuration.
  • a conformational isomer refers to a stereoisomer resulting from the rotation of a single bond.
  • the "prodrug” of the present invention refers to a compound which is converted into a compound of the present invention by reaction with an enzyme, gastric acid or the like under physiological conditions of a living body, that is, a compound which is converted into a compound of the invention by oxidation, reduction, hydrolysis or the like of an enzyme. And/or a compound which converts to the compound of the invention by a hydrolysis reaction such as gastric acid or the like.
  • the "pharmaceutically acceptable salt” of the present invention means a pharmaceutically acceptable salt of the compound of the present invention and an acid, which includes, but is not limited to, phosphoric acid, sulfuric acid, hydrochloric acid, hydrobromic acid, citric acid, and Malay. Acid, malonic acid, mandelic acid, succinic acid, fumaric acid, acetic acid, lactic acid, nitric acid, and the like.
  • a "pharmaceutical composition” is meant to comprise any one of the compounds described herein, including isomers, prodrugs, solvates, pharmaceutically acceptable salts or chemically protected forms thereof, and one or more A mixture of pharmaceutically acceptable carriers.
  • the "pharmaceutically acceptable carrier” of the present invention means a carrier which does not cause significant irritation to an organism and does not interfere with the biological activity and properties of the administered compound, and includes a solvent, a diluent or other excipient, a dispersing agent, and a surface active agent. Agents, isotonic agents, thickeners or emulsifiers, preservatives, solid binders, lubricants, and the like. Unless any conventional carrier medium is incompatible with the compounds of the invention.
  • pharmaceutically acceptable carriers include, but are not limited to, sugars such as lactose, glucose, and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives, such as sodium carboxymethylcellulose, And cellulose and cellulose acetate; malt, gelatin and the like.
  • Excipient refers to an inert substance that is added to a pharmaceutical composition to further facilitate administration of the compound.
  • Excipients may include calcium carbonate, calcium phosphate, various sugars, and various types of starch, cellulose. Derivatives, gelatin, vegetable oil, polyethylene glycol.
  • the "application in the preparation of a medicament for treating and/or preventing a tumor” of the present invention means that the growth, development and/or metastasis of the tumor can be inhibited, and the therapeutically effective dose is mainly administered to a human or animal in need thereof.
  • the compounds of the invention inhibit, slow or reverse the growth, progression or spread of a tumor in a subject.
  • the compounds of the present invention refer to all compounds of the general formula of the present invention, including the compounds of the formula I, formula Ia, formula Ib, formula Ic or formula Id and specific compounds.
  • the product of the step 2 (1.59 g, 3.3 mmol), potassium carbonate (1.82 g, 13.2 mmol), and 20 ml of methanol were mixed in a reactor, and the mixture was stirred at room temperature for 3 hours under an inert gas atmosphere.
  • the reaction completed the methanol was removed by rotary evaporation, ethyl acetate and the organic layer was extracted with water, combined, washed with saturated NaCl solution, dried over anhydrous added Na 2 SO 4. The organic solution was then concentrated on a rotary evaporator.
  • Methyl 3-amino-6-bromopyrazine-2-carboxylate (4.62 g, 20 mmol), aqueous hydrobromic acid (48%, 24 ml), acetic acid (3.2 ml) was added to the mixture and cooled to -5 °C.
  • Methyl 3,6-dibromopyrazine-2-carboxylate (5.0 g, 17 mmol), tetrahydrofuran (100 ml) was added to the reactor and cooled to -78 °C.
  • Diisobutylaluminum hydride (34 ml, 34 mmol) was slowly added dropwise, and the mixture was reacted at -78 ° C for 2 h. The reaction was completed, and quenched by the addition of glacial acetic acid at -78 ° C.
  • Step 2 was added to the reactor to give 1-((3-tert-butoxycarbonyl-3,8-diazabicyclo[3.2.1]octane-8-yl)methyl)-2-trifluoromethyl 4-Nitrobenzene (8 g, 19.2 mmol), amine chloride (10 g, 190 mmol), iron powder (2 g), ethanol (50 mL), refluxed for 2 h. After completion of the reaction, filtration, solvent was distilled off under reduced pressure, water was added and extracted with ethyl acetate, washed with saturated aqueous NaCl, dried over anhydrous Na 2 SO 4, filtered, rotary evaporation, purified by column chromatography to give the title compound.
  • Step 4 was added to the reactor to give 3-ethynyl-4-methyl-N-(4-((3-tert-butoxycarbonyl-3,8-diazabicyclo[3.2.1]octane-8) -Methyl)-3-(trifluoromethyl)phenyl)benzamide (5 g, 9.4 mmol), 40% aqueous formaldehyde (10 mL), EtOAc (50 mL). After completion of the reaction, water was added and extracted with ethyl acetate, washed with saturated aqueous NaCl, dried over anhydrous Na 2 SO 4, filtered, rotary evaporation, purified by column chromatography to give the title compound.
  • Step 6 3-((1H-pyrrolo[2,3-b]pyrazin-5-yl)ethynyl)-4-methyl-N-(4-((3-methyl-3,8-di) Azabicyclo[3.2.1]octane-8-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide
  • Imatinib was prepared according to the method described in Chinese Patent No. CN1043531C and identified by hydrogen spectroscopy and mass spectrometry.
  • Ponatinib was purchased from Shanghai Xinkuo Chemical Technology Co., Ltd., and Ponatinib hydrochloride was prepared according to the method of Example 3 of the present invention and passed through hydrogen spectrum. And mass spectrometry identification.
  • the compounds of the above representative examples 2, 4, 5, 8, 9, 10 and imatinib and Ponatinib were used. Each compound was dissolved in DMSO to 10 mM, diluted to 50 ⁇ M with complete medium, and then diluted to 10 ⁇ M with complete medium containing 0.1% DMSO, and then diluted 10-fold in total for 10 concentrations.
  • K562 leukemia cells purchased from ATCC, USA
  • Imatinib-tolerant K562 leukemia cells purchased from ATCC, USA
  • DMSO Dimethyl sulfoxide
  • Luminescent cell viability assay kit CellTiter- Luminescent Cell Viability Assay Kit, purchased from Promega, USA;
  • IMEM medium (IMEM medium), purchased from Gibco, USA;
  • Penicillin/streptomycin (Pen/Strep), purchased from Gibco, USA;
  • Fetal bovine serun purchased from Gibco, USA;
  • 0.25% containing EDTA trypsin (0.25% Trypsin-EDTA), purchased from Gibco, USA;
  • 10cm cell culture dish (10cm cell culture dish), purchased from Corning, USA;
  • 50mL centrifuge tube 50mL centrifuge tube, purchased from Corning, USA;
  • Phosphate Buffered Saline was prepared weekly.
  • the compound of the present invention has a strong inhibitory activity against leukemia cells with an IC 50 value at the nM level.
  • the compounds of the invention are comparable to Ponatinib and far superior to imatinib.
  • the compounds of the invention exhibited better inhibitory activity than Ponatinib.
  • This experiment tested the inhibition of ABL (T315I) kinase activity by the compounds prepared in the examples of the present invention, using imatinib as a control.
  • Imatinib was prepared by the method described in Chinese Patent No. CN1043531C and identified by hydrogen spectroscopy and mass spectrometry.
  • ABL (T315I) tyrosine kinase activity was tested using a commercially available human ABL T315I mutant enzyme (Human ABL1 (T315I), active, Cat. #14-522, Millipore Corporation, USA). Kinase activity assays were performed according to the manufacturer's instructions.
  • the Peptide substrate was Abltide (EAIYAAPFAKKK) and was purchased from Millipore Corporation of the United States.
  • Ion exchange chromatography paper (P81) was purchased from Whatman Company of the United Kingdom.
  • [ ⁇ -33P] ATP was purchased from Perkin Elmer.
  • the compound of the present invention and imatinib were serially diluted 3 times from 1 ⁇ M, respectively, for a total of 10 concentrations (50.8 pM, 152.0 pM, 457.0 pM, 1.37 nM, 4.12 nM, 12.3 nM, 37.0 nM, 111.0 nM, 333.0 nM and 1.0 ⁇ M).
  • 5.0 ⁇ M Abltide was added to each well and then human T315I mutant enzyme was added.
  • [ ⁇ - 33 P]ATP was added at room temperature to a final concentration of 1.0 ⁇ M, and the reaction was carried out for 120 minutes. A 20 ⁇ l aliquot was transferred to a P81 ion exchange chromatography paper. The chromatography paper was then washed thoroughly 3 times with a 0.75% phosphoric acid solution and once with acetone. Finally, a gamma- 33P radioactivity assay was performed. The experimental results are shown in Table 2.
  • the compound of the present invention not only has a very good effect on leukemia cells without mutation, but also can significantly inhibit the T315I mutant enzyme, and thus is a broad-spectrum BCR-ABL inhibitor.
  • TKI tyrosine kinase inhibitor
  • CML chronic myeloid leukemia
  • blast blast
  • accelerated Philadelphia chromosome-positive
  • Ph+ Philadelphia chromosome-positive
  • the compounds of the invention prepared using the above representative examples 3 and 6 were used.
  • the oral drug formulation is dissolved in physiological saline to prepare a suspension of 3 mg/ml;
  • mice Male Sprague-Dawley rats, 3 in each group, weighing 150-250 g, were provided by Shanghai Xipuer-Beikai Experimental Animal Co., Ltd. The rats in the test group were given an environmental adaptation period of 2 to 4 days before the experiment, and were fasted for 8-12 hours before administration, and given water for 2 hours after administration, and fed after 4 hours.
  • Acetonitrile (chromatographically pure): produced by Spectrum;
  • step 2) Take 3 rats in step 1), intragastric administration (I.G.) to give Example 3 compound 15mg / kg;
  • the intravenous vein (Intravenous administration, I.V.) was given the compound of Example 3 3mg / kg;
  • the intravenous vein (Intravenous administration, I.V.) was given the compound of Example 6 5mg / kg;
  • the fundus venous plexus was continuously taken from the EP tube with heparin. After centrifugation at 8000 rpm/min for 5 min, the upper layer of plasma was taken. Cryopreservation at 20 ° C, to be analyzed by LC-MS/MS.
  • the oral pharmaceutical formulation was: physiological saline dissolved.
  • mice Male mice, 24, weighing 18 ⁇ 2 g, were purchased from Qinglong Mountain Animal Breeding Farm in Jiangning District, Nanjing. The test mice were given an environmental adaptation period of 2 to 4 days before the experiment, and were fasted for 8-12 hours before administration, and given water for 2 hours after administration, and fed after 4 hours.
  • Ultrapure water Milli-Q ultra pure water purifier (Millipore Inc) instrument homemade;
  • Milli-Q Ultra Water Purifier (Millipore Inc); LT501 Electronic Balance.
  • mice were randomly divided into 3 groups: blank control group, Ponatinib hydrochloride drug group, and Example 6 drug group, 6 rats in each group;
  • mice are administered by intragastric administration, the administration method is: day 0-2, the administration dose is 10 mg/kg; on the 3-5th day, the administration dose is 20 mg/kg; on the sixth to the ninth day, the administration dose is 40mg/kg;
  • * indicates p ⁇ 0.05 compared to the blank control group.
  • the above subacute toxicity test results showed that the Ponatinib group had a significant effect on the body weight of the mice compared with the blank control group, and the P value was ⁇ 0.05, while the compound of the present invention had no effect on the body weight of the mice and showed extremely low toxicity.
  • the medicament of the present invention is significantly superior to Ponatinib in terms of toxic side effects.

Abstract

本发明属于化学医药领域，具体涉及式I所示的一类具有BCR-ABL激酶抑制活性的化合物或其药学可接受的盐、异构体、溶剂合物、结晶或前药，以及含有这些化合物的药物组合物和这些化合物或组合物在药物制备中的应用。本发明的化合物对BCR-ABL激酶具有较强的抑制作用，可以用于治疗例如肿瘤性疾病。

Description

BCR-ABL激酶抑制剂及其应用 技术领域
本发明属于化学医药领域，具体涉及一类具有BCR-ABL激酶抑制活性的化合物或其药学可接受的盐、异构体、溶剂合物、结晶或前药，以及含有这些化合物的药物组合物和这些化合物或组合物在药物制备中的应用。
背景技术
蛋白酪氨酸激酶(PTKs)是一类能够催化ATP上γ-磷酸转移到蛋白酪氨酸残基上的激酶，通过催化多种蛋白酪氨酸残基上的酚羟基发生磷酸化，进而启动功能蛋白作用的蛋白质酶系。蛋白酪氨酸激酶(PTKs)在细胞内的信号传导通路中占据着十分重要的地位，调节细胞生长、分化、死亡等一系列生理生化过程。蛋白酪氨酸激酶的异常表达可以导致细胞增殖调节发生紊乱，进而导致肿瘤的发生。此外，蛋白酪氨酸激酶的异常表达还与肿瘤的侵袭和转移，肿瘤新生血管的生成，肿瘤的化疗抗药性密切相关。酪氨酸激酶抑制剂可作为三磷酸腺苷(ATP)与酪氨酸激酶结合的竞争性抑制剂，竞争性结合酪氨酸激酶，阻断酪氨酸激酶的活性，抑制细胞增殖，已经有数种酪氨酸蛋白激酶抑制剂成功地得到了开发。
慢性粒细胞白血病(CML)患者中，22号染色体长臂易位至9号染色体，形成费城染色体，并导致BCR基因和ABL基因融合形成BCR-ABL融合基因，表达BCR-ABL蛋白酪氨酸激酶，在细胞信号转导和转化中通过磷酸化等作用，促使CML成熟粒细胞无限增生。BCR-ABL在正常细胞中并不表达，已经成为了治疗CML的理想药物靶标。目前，BCR-ABL酪氨酸激酶抑制剂已经成为大多数慢性粒细胞白血病的一线治疗药物。
伊马替尼是第一个分子靶向治疗的蛋白酪氨酸激酶抑制剂，体内外均可在细胞水平上抑制BCR-ABL酪氨酸激酶，选择性抑制BCR-ABL阳性细胞系细胞以及费城染色体阳性(Ph+)的慢性髓性白血病(CML)和急性淋巴细胞白血病(ALL)病人的新鲜白血病细胞的增殖，诱导其凋亡。伊马替尼的开发及临床使用开启了肿瘤分子靶向的新时代，但是长期服用伊马替尼，会产生耐药性，导致病情复发。随着伊马替尼在临床上的广泛应用，耐药问题日益突出。获得性耐受的主要原因是由于 BCR-ABL的点突变导致伊马替尼不能与BCR-ABL结合而产生的。并且，已发现上百种BCR-ABL点突变与伊马替尼耐药相关，其中15～20％的伊马替尼耐受患者存在T315I突变。
伊马替尼耐药性的出现，激起了新一代酪氨酸激酶抑制剂的研发热潮，以期开发出更优的用于治疗白血病，例如耐药或不耐药的各期CML、Ph+ALL的新的药物。
发明内容
本发明的目的是提供通式I的一类具有广谱的BCR-ABL激酶抑制效果的化合物或其药学可接受的盐、异构体、溶剂合物、结晶或前药，
Figure PCTCN2014088911-appb-000001
本发明的另一个目的是提供制备本发明的通式I的化合物或其药学可接受的盐、异构体、溶剂合物、结晶或前药的方法。
本发明的再一个目的是提供包含本发明的通式I的化合物或其药学可接受的盐、异构体、溶剂合物、结晶或前药和药学可接受的载体的组合物，以及包含本发明的通式I的化合物或其药学可接受的盐、异构体、溶剂合物、结晶或前药和另一种或多种蛋白酪氨酸激酶抑制剂的组合物。
本发明的还一个目的是提供本发明的通式I的化合物或其药学可接受的盐、异构体、溶剂合物、结晶或前药治疗和/或预防肿瘤的方法，以及本发明的通式I的化合物或其药学可接受的盐、异构体、溶剂合物、结晶或前药在制备用于治疗和/或预防肿瘤的药物中的应用。
针对上述目的，本发明提供以下技术方案：
第一方面，本发明提供通式I的化合物或其药学可接受的盐、异构体、溶剂 合物、结晶或前药，
Figure PCTCN2014088911-appb-000002
其中：
X选自N和C(R5)，其中R5选自氢、卤素、C1-6烷基、卤代C1-6烷基；
Y选自N和C(R6)，其中R6选自氢、卤素、C1-6烷基、卤代C1-6烷基；
R1选自氢、烷基、烷氧基、卤代烷基、卤代烷氧基、-OH、-NH2、卤素和CN；
R2选自氢、烷基、烷氧基、卤代烷基、卤代烷氧基、-OH、-NH2、卤素和CN；
W选自C1-6亚烷基、-C(O)-，与R4形成4-8元环烷基或不存在；
R3选自取代或未取代的五元、六元、七元和八元含氮杂环基；
R4选自氢、烷基、卤代烷基、或与W一起形成4-8元环烷基；
其条件是排除以下化合物：
3-((1H-吡咯并[2,3-b]吡嗪-5-基)乙炔基)-4-甲基-N-[4-((4-甲基呱嗪-1-基)甲基)-3-三氟甲基苯基]苯甲酰胺。
在一些优选的实施方案中，本发明的化合物为通式I的化合物及其药学可接受的盐、异构体、溶剂合物、结晶或前药，其中：
X选自N和C(R5)，其中R5选自氢、氟、氯、溴、C1-4烷基、卤代C1-4烷基；
Y选自N和C(R6)，其中R6选自氢、氟、氯、溴、C1-4烷基、卤代C1-4烷基；
R1选自氢、C1-4烷基、C1-4烷氧基、卤代C1-4烷基、卤代C1-4烷氧基、-OH、-NH2、氟、氯、溴和CN；
R2选自氢、C1-4烷基、C1-4烷氧基、卤代C1-4烷基、卤代C1-4烷氧基、-OH、-NH2、氟、氯、溴和CN；
W选自C1-4亚烷基、-C(O)-，与R4形成4-8元环烷基或不存在；
R3选自取代或未取代的含有1、2或3个氮原子的氮杂环己烷，所述取代基选自烷基、羟基、羟烷基、烷氧基、氨基、单烷基氨基、双烷基氨基、酰氨基、 烷基酰氨基、芳基酰氨基、杂芳基酰氨基、卤素、卤素取代的烷基、卤素取代的烷氧基，优选地所述取代基选自C1-6烷基、羟基、羟C1-6烷基、C1-6烷氧基、氨基、单C1-6烷基氨基、双C1-6烷基氨基、酰氨基、C1-6烷基酰氨基、芳基酰氨基、杂芳基酰氨基、卤素、卤素取代的C1-6烷基、卤素取代的C1-6烷氧基。
R4选自氢、C1-6烷基、卤代C1-6烷基、或与W一起构成环戊烷基、环丁烷基、环己烷基、环庚烷基。
在一些优选的实施方案中，本发明的化合物为通式I的化合物及其药学可接受的盐、异构体、溶剂合物、结晶或前药，其中：
X选自N和C(R5)，其中R5选自氢、氟、氯、溴、C1-4烷基、卤代C1-4烷基；
Y选自N和C(R6)，其中R6选自氢、氟、氯、溴、C1-4烷基、卤代C1-4烷基；
R1选自氢、C1-4烷基、C1-4烷氧基、卤代C1-4烷基、卤代C1-4烷氧基、-OH、-NH2、氟、氯、溴和CN；
R2选自氢、C1-4烷基、C1-4烷氧基、卤代C1-4烷基、卤代C1-4烷氧基、-OH、-NH2、氟、氯、溴和CN；
W选自C1-4亚烷基、-C(O)-，与R4形成4-8元环烷基或不存在；
R3选自呱嗪基、吡啶基、氮杂双环烷基、咪唑基、吡唑基、吡咯基、***基、哒嗪基、嘧啶基、吡嗪基、呱啶基、三嗪基，或取代的呱嗪基、吡啶基、氮杂双环烷基、咪唑基、吡唑基、吡咯基、***基、哒嗪基、嘧啶基、吡嗪基、呱啶基、三嗪基，其中所述取代选自烷基、羟基、羟烷基、烷氧基、氨基、单烷基氨基、双烷基氨基、酰氨基、烷基酰氨基、芳基酰氨基、杂芳基酰氨基、卤素、卤素取代的烷基、卤素取代的烷氧基，优选地所述取代基选自C1-6烷基、羟基、羟C1-6烷基、C1-6烷氧基、氨基、单C1-6烷基氨基、双C1-6烷基氨基、酰氨基、C1-6烷基酰氨基、芳基酰氨基、杂芳基酰氨基、卤素、卤素取代的C1-6烷基、卤素取代的C1-6烷氧基。
R4选自氢、C1-6烷基、卤代C1-6烷基、或与W一起构成环戊烷基、环丁烷基、环己烷基、环庚烷基。
更优选地，本发明的化合物包括通式I的化合物及其药学可接受的盐、异构体、溶剂合物、结晶或前药，其中：
X选自N和C(R5)，其中R5选自氢、氟、氯、溴、C1-3烷基、卤代C1-3烷基；
Y选自N和C(R6)，其中R6选自氢、氟、氯、溴、C1-3烷基、卤代C1-3烷基；
R1选自氢、C1-3烷基、C1-3烷氧基、卤代C1-3烷基、卤代C1-3烷氧基、-OH、-NH2、氟、氯、溴和CN；
R2选自氢、C1-3烷基、C1-3烷氧基、卤代C1-3烷基、卤代C1-3烷氧基、-OH、-NH2、氟、氯、溴和CN；
W选自C1-3亚烷基(例如-CH2-，-CH2-CH2-)、-C(O)-，与R4形成环戊烷基或不存在；
R3选自呱嗪基、呱啶-4-基、二氮杂双环辛烷基例如3,8-二氮杂双环[3.2.1]辛烷基，所述的呱嗪基、呱啶-4-基、二氮杂双环辛烷基可以被一个或多个C1-6烷基、C1-6烷氧基取代，例如被一个或多个甲基、乙基、丙基、异丙基、甲氧基、乙氧基或丙氧基等取代；
R4选自氢、C1-4烷基、卤代C1-4烷基、或与W一起构成环戊烷基。
在上述通式I化合物的一些实施方案中，其中X为N，Y为N。
在上述通式I化合物的一些实施方案中，其中X为N，Y为C(R6)，所述的R6选自氢、卤素、C1-6烷基、卤代C1-6烷基，优选地R6选自氢、氟、氯、溴、C1-4烷基、卤代C1-4烷基，更优选地R6选自氢、氟、氯、溴、C1-3烷基、卤代C1-3烷基。
在上述通式I化合物的一些实施方案中，其中X为C(R5)，Y为N，所述的R5选自氢、卤素、C1-6烷基、卤代C1-6烷基，优选地R5选自氢、氟、氯、溴、C1-4烷基、卤代C1-4烷基，更优选地R5选自氢、氟、氯、溴、C1-3烷基、卤代C1-3烷基。
在上述通式I化合物的一些实施方案中，其中X为C(R5)，Y为C(R6)，所述的R5和R6各自独立地选自氢、卤素、C1-6烷基、卤代C1-6烷基，优选地R5和R6各自独立地选自氢、氟、氯、溴、C1-4烷基、卤代C1-4烷基，更优选地R5和R6各自独立地选自氢、氟、氯、溴、C1-3烷基、卤代C1-3烷基。
优选地，本发明提供通式Ia的化合物或其药学可接受的盐、异构体、溶剂合物、结晶或前药，
Figure PCTCN2014088911-appb-000003
其中：
X选自N和C(R5)，其中R5选自氢、卤素、C1-6烷基、卤代C1-6烷基；
Y选自N和C(R6)，其中R6选自氢、卤素、C1-6烷基、卤代C1-6烷基；
R1选自氢、烷基、烷氧基、卤代烷基、卤代烷氧基、-OH、-NH2、卤素和CN；
R2选自氢、烷基、烷氧基、卤代烷基、卤代烷氧基、-OH、-NH2、卤素和CN；
W选自C1-6亚烷基、-C(O)-或不存在；
R3选自取代或未取代的五元、六元、七元和八元含氮杂环基，优选地R3为取代或未取代的含有1、2或3个氮原子的氮杂环己烷，进一步优选地R3为呱嗪基、吡啶基、氮杂双环烷基、咪唑基、吡唑基、吡咯基、***基、哒嗪基、嘧啶基、吡嗪基、呱啶基、三嗪基，或取代的呱嗪基、吡啶基、氮杂双环烷基、咪唑基、吡唑基、吡咯基、***基、哒嗪基、嘧啶基、吡嗪基、呱啶基、三嗪基，其中所述取代基选自C1-6烷基、羟基、羟C1-6烷基、C1-6烷氧基、氨基、单C1-6烷基氨基、双C1-6烷基氨基、酰氨基、C1-6烷基酰氨基、芳基酰氨基、杂芳基酰氨基、卤素、卤素取代的C1-6烷基、卤素取代的C1-6烷氧基，更优选地R3为呱嗪基、呱啶-4-基、二氮杂双环烷基如3,8-二氮杂双环[3.2.1]辛烷基，或被一个或多个C1-6烷基、C1-6烷氧基取代的呱嗪基、呱啶-4-基、二氮杂双环烷基，例如R3为4-甲基呱嗪-1-基、呱啶-4-基、1-甲基呱啶-4-基、3,8-二氮杂双环[3.2.1]辛烷-8-基、1-甲基-3,8-二氮杂双环[3.2.1]辛烷-8-基；
R4选自氢、C1-6烷基、卤代C1-6烷基；
其条件是排除以下化合物：
3-((1H-吡咯并[2,3-b]吡嗪-5-基)乙炔基)-4-甲基-N-[4-((4-甲基呱嗪-1-基)甲基)-3-三氟甲基苯基]苯甲酰胺。
优选地，本发明提供通式Ib的化合物或其药学可接受的盐、异构体、溶剂合物、结晶或前药，
Figure PCTCN2014088911-appb-000004
其中：
X选自N和C(R5)，其中R5选自氢、卤素、C1-6烷基、卤代C1-6烷基；
Y选自N和C(R6)，其中R6选自氢、卤素、C1-6烷基、卤代C1-6烷基；
R1选自氢、烷基、烷氧基、卤代烷基、卤代烷氧基、-OH、-NH2、卤素和CN；
R2选自氢、烷基、烷氧基、卤代烷基、卤代烷氧基、-OH、-NH2、卤素和CN；
W选自C1-6亚烷基、-C(O)-或不存在；
R3选自取代或未取代的五元、六元、七元和八元含氮杂环基，优选地R3为取代或未取代的含有1、2或3个氮原子的氮杂环己烷，进一步优选地R3为呱嗪基、吡啶基、氮杂双环烷基、咪唑基、吡唑基、吡咯基、***基、哒嗪基、嘧啶基、吡嗪基、呱啶基、三嗪基，或取代的呱嗪基、吡啶基、氮杂双环烷基、咪唑基、吡唑基、吡咯基、***基、哒嗪基、嘧啶基、吡嗪基、呱啶基、三嗪基，其中所述取代基选自C1-6烷基、羟基、羟C1-6烷基、C1-6烷氧基、氨基、单C1-6烷基氨基、双C1-6烷基氨基、酰氨基、C1-6烷基酰氨基、芳基酰氨基、杂芳基酰氨基、卤素、卤素取代的C1-6烷基、卤素取代的C1-6烷氧基，更优选地R3为呱嗪基、呱啶-4-基、二氮杂双环烷基，或被一个或多个C1-6烷基、C1-6烷氧基取代的呱嗪基、呱啶-4-基、二氮杂双环烷基，例如R3为4-甲基呱嗪-1-基、呱啶-4-基、1-甲基呱啶-4-基、3,8-二氮杂双环[3.2.1]辛烷-8-基、1-甲基-3,8-二氮杂双环[3.2.1]辛烷-8-基；
R4选自氢、C1-6烷基、卤代C1-6烷基。
优选地，本发明提供通式Ic的化合物或其药学可接受的盐、异构体、溶剂合物、结晶或前药，
Figure PCTCN2014088911-appb-000005
其中：
X选自N和C(R5)，其中R5选自氢、卤素、C1-6烷基、卤代C1-6烷基；
Y选自N和C(R6)，其中R6选自氢、卤素、C1-6烷基、卤代C1-6烷基；
R1选自氢、烷基、烷氧基、卤代烷基、卤代烷氧基、-OH、-NH2、卤素和CN；
R2选自氢、烷基、烷氧基、卤代烷基、卤代烷氧基、-OH、-NH2、卤素和CN；
R3选自取代或未取代的五元、六元、七元和八元含氮杂环基，优选地R3为取代或未取代的含有1、2或3个氮原子的氮杂环己烷，进一步优选地R3为呱嗪基、吡啶基、氮杂双环烷基、咪唑基、吡唑基、吡咯基、***基、哒嗪基、嘧啶基、吡嗪基、呱啶基、三嗪基，或取代的呱嗪基、吡啶基、氮杂双环烷基、咪唑基、吡唑基、吡咯基、***基、哒嗪基、嘧啶基、吡嗪基、呱啶基、三嗪基，其中所述取代基选自C1-6烷基、羟基、羟C1-6烷基、C1-6烷氧基、氨基、单C1-6烷基氨基、双C1-6烷基氨基、酰氨基、C1-6烷基酰氨基、芳基酰氨基、杂芳基酰氨基、卤素、卤素取代的C1-6烷基、卤素取代的C1-6烷氧基，更优选地R3为呱嗪基、呱啶-4-基、二氮杂双环烷基，或被一个或多个C1-6烷基、C1-6烷氧基取代的呱嗪基、呱啶-4-基、二氮杂双环烷基，例如R3为4-甲基呱嗪-1-基、呱啶-4-基、1-甲基呱啶-4-基、3,8-二氮杂双环[3.2.1]辛烷-8-基、1-甲基-3,8-二氮杂双环[3.2.1]辛烷-8-基。
优选地，本发明提供通式Id的化合物或其药学可接受的盐、异构体、溶剂合物、结晶或前药，
Figure PCTCN2014088911-appb-000006
其中：
X选自N和C(R5)，其中R5选自氢、卤素、C1-6烷基、卤代C1-6烷基；
Y选自N和C(R6)，其中R6选自氢、卤素、C1-6烷基、卤代C1-6烷基；
R1选自氢、烷基、烷氧基、卤代烷基、卤代烷氧基、-OH、-NH2、卤素和CN；
R2选自氢、烷基、烷氧基、卤代烷基、卤代烷氧基、-OH、-NH2、卤素和CN；
R3选自取代或未取代的五元、六元、七元和八元含氮杂环基，优选地R3为取代或未取代的含有1、2或3个氮原子的氮杂环己烷，进一步优选地R3为呱嗪基、吡啶基、氮杂双环烷基、咪唑基、吡唑基、吡咯基、***基、哒嗪基、嘧啶 基、吡嗪基、呱啶基、三嗪基，或取代的呱嗪基、吡啶基、氮杂双环烷基、咪唑基、吡唑基、吡咯基、***基、哒嗪基、嘧啶基、吡嗪基、呱啶基、三嗪基，其中所述取代基选自C1-6烷基、羟基、羟C1-6烷基、C1-6烷氧基、氨基、单C1-6烷基氨基、双C1-6烷基氨基、酰氨基、C1-6烷基酰氨基、芳基酰氨基、杂芳基酰氨基、卤素、卤素取代的C1-6烷基、卤素取代的C1-6烷氧基，更优选地R3为呱嗪基、呱啶-4-基、二氮杂双环烷基，或被一个或多个C1-6烷基、C1-6烷氧基取代的呱嗪基、呱啶-4-基、二氮杂双环烷基，例如R3为4-甲基呱嗪-1-基、呱啶-4-基、1-甲基呱啶-4-基、3,8-二氮杂双环[3.2.1]辛烷-8-基、1-甲基-3,8-二氮杂双环[3.2.1]辛烷-8-基。
优选地，根据本发明，在一些实施方案中，在通式I、Ia、Ib、Ic、Id中，R1选自氢、烷基、烷氧基、卤代烷基、卤素和CN，特别是R1选自氢、C1-6烷基、C1-6烷氧基、卤代C1-6烷基、卤素和CN。
优选地，根据本发明，在一些实施方案中，在通式I、Ia、Ib、Ic、Id中，R2选自氢、烷基、卤代烷基、卤素和CN，特别是R2选自氢、C1-6烷基、卤代C1-6烷基、卤素和CN。
优选地，根据本发明，在一些实施方案中，在通式I、Ia、Ib、Ic、Id中，R3选自4-甲基呱嗪-1-基、呱啶-4-基、1-甲基呱啶-4-基、3,8-二氮杂双环[3.2.1]辛烷-8-基、1-甲基-3,8-二氮杂双环[3.2.1]辛烷-8-基。
优选地，根据本发明，在一些实施方案中，在通式I、Ia、Ib、Ic、Id中，R4选自甲基和三氟甲基。
优选地，根据本发明，在一些实施方案中，在通式I、Ia、Ib、Ic、Id中，W与R4一起构成环戊烷基。
优选地，根据本发明，在一些实施方案中，在通式I、Ia、Ib、Ic、Id中，R5选自氢、卤素。
优选地，根据本发明，在一些实施方案中，在通式I、Ia、Ib、Ic、Id中，R6选自氢、卤素。
优选地，根据本发明，在一些实施方案中，在通式I、Ia、Ib、Ic、Id中，R1选自氢、甲基、三氟甲基、甲氧基、乙氧基、丙氧基或异丙氧基。
优选地，根据本发明，在一些实施方案中，在通式I、Ia、Ib、Ic、Id中，R2选自氢、甲基、乙基、丙基和异丙基。
优选地，根据本发明，在一些实施方案中，在通式I、Ia、Ib、Ic、Id中，R5选自氢、氟。
优选地，根据本发明，在一些实施方案中，在通式I、Ia、Ib、Ic、Id中，R6选自氢、氟。
本发明提供了以下具体化合物：
Figure PCTCN2014088911-appb-000007
Figure PCTCN2014088911-appb-000008
另一方面，本发明提供本发明的通式化合物的制备方法。通式I的化合物的制备方法包括如下步骤：
(1)式5的中间体的制备：
Figure PCTCN2014088911-appb-000009
a)式1的化合物与式2的化合物反应得到式3的中间体；
b)式3的中间体与三甲基硅乙炔反应得到式4的中间体；
c)式4的中间体脱去三甲基硅烷基得到式5的中间体；
(2)通式I的化合物的制备：
Figure PCTCN2014088911-appb-000010
d)式5的中间体与式6的中间体反应得到通式I的化合物。
其中，R1、R2、R3、R4、W、X、Y具有通式I中的含义，M选自氯、溴、碘。
第三方面，本发明提供药物组合物，其包含本发明的化合物或其药学可接受的盐、异构体、溶剂合物、结晶或前药。
在一些实施方案中，本发明提供本发明的化合物或其药学可接受的盐、异构体、溶剂合物、结晶或前药及包含本发明的化合物或其药学可接受的盐、异构体、溶剂合物、结晶或前药的药物组合物，所述化合物或药物组合物用于治疗或预防癌症，所述癌症包括实体瘤以及各种形式的白血病，包括对其他治疗抵抗的白血病。
在一些实施方案中，本发明提供药物组合物，其包含本发明的化合物、异构体、溶剂合物、结晶或前药，还包含选自下列组成的一种或多种：酪氨酸蛋白酶抑制剂、EGFR抑制剂、VEGFR抑制剂、BCR-ABL抑制剂、c-kit抑制剂、c-Met抑制剂、Raf抑制剂、MEK抑制剂、组蛋白去乙酰酶抑制剂、VEGF抗体、EGF抗体、HIV蛋白激酶抑制剂、HMG-CoA还原酶抑制剂等。
可以将本发明的化合物、异构体、溶剂合物、结晶或前药与药学上可接受的载体、稀释剂或赋形剂混合制备成药物制剂，以适合于经口或胃肠外给药。给药方法包括，但不限于皮内、肌内、腹膜内、静脉内、皮下、鼻内和经口途径。所述制剂可以通过任何途径施用，例如通过输注或推注，通过经上皮或皮肤粘膜(例如口腔粘膜或直肠等)吸收的途径施用。给药可以是全身的或局部的。经口施用制剂的实例包括固体或液体剂型，具体而言，包括片剂、丸剂、粒剂、粉剂、胶囊剂、糖浆、乳剂、混悬剂等。所述制剂可通过本领域已知的方法制备，且包含药物制剂领域常规使用的载体、稀释剂或赋形剂。
第四方面，本发明提供本发明的化合物、异构体、溶剂合物、结晶或前药或本发明的药物组合物治疗和/或预防肿瘤的方法和在制备预防和/或***药物中的应用，包括向肿瘤易发人群或肿瘤患者施用本发明的化合物、异构体、溶剂合物、结晶或前药或者包含本发明的化合物、异构体、溶剂合物、结晶或前药的药物组合物，以有效降低肿瘤发生率、延长肿瘤患者生命。
在一些实施方案中，本发明提供用于治疗和/或预防肿瘤的方法，包括向有此需要的个体给予治疗和/或预防有效量的本发明的化合物、异构体、溶剂合物、结晶或前药或本发明的药物组合物。可以向有需要的哺乳动物给予本发明的化合物、异构体、溶剂合物、结晶或前药或本发明的药物组合物以抑制肿瘤的生长、发展和/或转移，所述肿瘤包括实体瘤，例如乳腺癌、结肠癌、胃癌、胰腺癌、中枢神经***肿瘤和头颈癌以及各种形式的白血病，包括对其他治疗抵抗如对伊马替尼或其它激酶抑制剂抵抗的白血病和其它癌症，所述激酶被本发明的化合物或组合物所抑制。
术语说明
本发明的“烷基”是指直链、支链或环状的饱和烃基，优选为C1-6烷基，例如，合适的C1-6烷基基团包括但不限于甲基、乙基、正丙基、异丙基、环丙基、 正丁基、异丁基、叔丁基、环丁基、正戊基、异戊基、环戊基、环己基、正己基。在本文中，所述烷基进一步优选为C1-3烷基，合适的C1-3烷基为甲基、乙基、丙基、异丙基、环丙基。如本文所用，本发明中的烷基包括取代或未取代的烷基，所述烷基可任选被一个或多个选自以下的基团取代：烷基、烷氧基、芳氧基、烷氨基、芳基氨基、卤素、羟基、氨基、硝基、氰基、烷基酰基、氨基酰基、烷氨基酰基、磺酰基、亚磺酰基、巯基、芳基或杂芳基。
本发明的“烷氧基”是指烷基-O-，优选为C1-6烷基-O-，进一步优选为C1-3烷基-O-，合适的C1-3烷基-O-为甲氧基、乙氧基、丙氧基、异丙氧基。
本发明的“卤素”是指氟、氯、溴、碘，优选为氟、氯。
本发明的“卤代烷基”是指至少被一个卤素取代的烷基，优选为卤代C1-6烷基，进一步优选为卤代C1-3烷基，合适的卤代C1-3烷基为氯甲基、氟甲基、二氯甲基、二氟甲基、三氯甲基、三氟甲基、氯乙基、氟乙基、二氯乙基、二氟乙基、三氯乙基、三氟乙基。
本发明的“卤代烷氧基”是指至少被一个卤素取代的烷氧基，优选为至少被一个卤素取代的C1-6烷氧基，进一步优选为卤代C1-3烷氧基，合适的卤代C1-3烷氧基为氯甲氧基、氟甲氧基、二氯甲氧基、二氟甲氧基、三氯甲氧基、三氟甲氧基；二氯乙氧基、二氟乙氧基、三氯乙氧基、三氟乙氧基。
本发明的“五元、六元、七元、八元含氮杂环基”是指取代或未取代的具有至少一个环，总环原子数为五个、六个、七个、八个且含有至少一个氮原子的饱和、部分饱和和完全不饱和的杂环基团。优选地，所述“五元、六元、七元、八元含氮杂环基”为呱嗪基、吡啶基、氮杂双环烷基、咪唑基、吡唑基、吡咯基、***基、哒嗪基、嘧啶基、吡嗪基、呱啶基、三嗪基，或取代的呱嗪基、吡啶基、氮杂双环烷基、咪唑基、吡唑基、吡咯基、***基、哒嗪基、嘧啶基、吡嗪基、呱啶基、三嗪基，其中所述取代基选自烷基、羟基、羟烷基、烷氧基、氨基、单烷基氨基、双烷基氨基、酰氨基、烷基酰氨基、芳基酰氨基、杂芳基酰氨基、卤素、卤素取代的烷基、卤素取代的烷氧基，优选地所述取代基选自C1-6烷基、羟基、羟C1-6烷基、C1-6烷氧基、氨基、单C1-6烷基氨基、双C1-6烷基氨基、酰氨基、C1-6烷基酰氨基、芳基酰氨基、杂芳基酰氨基、卤素、卤素取代的C1-6烷基、卤素取代的C1-6烷氧基。
本发明的“4-8元环烷基”是指包含4-8个碳原子的单环或二环饱和烃基， 合适的环烷基包括环丁基、环戊基、环己基和环庚基等。其它合适的环烷基包括螺戊基、二环[2.1.0]戊基和二环[3.1.0]己基等。
本发明的“溶剂合物”在常规意义上是指溶质(如活性化合物、活性化合物的盐)和溶剂(如水)组合形成的复合物。溶剂是指本领域的技术人员所知的或容易确定的溶剂。如果是水，则溶剂合物通常被称作水合物，例如一水合物、二水合物、三水合物等。
本发明的“结晶”是指本发明所述的化合物形成的各种固体形态，包括晶型、无定形。
本发明的“异构体”包括化合物顺构型构体、构象异构体和对映异构体。构型异构体是指顺式或反式构型的顺反异构体。构象异构体是指由于单键旋转产生的立体异构体。
本发明的“前药”是指在生物体的生理条件下，由于与酶、胃酸等反应而转化成本发明的化合物的化合物，即通过酶的氧化、还原、水解等转化成本发明的化合物的化合物和/或通过胃酸等的水解反应等转化成本发明的化合物的化合物。
本发明的“药学可接受的盐”是指本发明的化合物与酸形成的药学上可接受的盐，所述的酸包括但不限于磷酸、硫酸、盐酸、氢溴酸、柠檬酸、马来酸、丙二酸、扁桃酸、琥珀酸、富马酸、醋酸、乳酸、硝酸等等。
本发明的“药物组合物”是指包含任何一种本文所述的化合物，包括异构体、前药、溶剂合物、药学上可接受的盐或其化学的保护形式，和一种或多种药学上可接受载体的混合物。
本发明的“药学上可接受的载体”是指对有机体不引起明显刺激性和不干扰所给予化合物的生物活性和性质的载体，包含溶剂、稀释剂或其它赋形剂、分散剂、表面活性剂、等渗剂、增稠剂或乳化剂、防腐剂、固体粘合剂、润滑剂等。除非任何常规载体介质与本发明化合物不相容。可以作为药学上可接受的载体的一些实例包括，但不限于糖类，如乳糖、葡萄糖和蔗糖；淀粉，如玉米淀粉和马铃薯淀粉；纤维素及其衍生物，如羧甲基纤维素钠、以及纤维素和乙酸纤维素；麦芽、明胶等。
本发明的“赋形剂”指加入到药用组合物中以进一步促进给予化合物的惰性物质。赋形剂可以包括碳酸钙、磷酸钙、多种糖类和多种类型的淀粉、纤维素 衍生物、明胶、植物油、聚乙二醇。
本发明的“在制备用于治疗和/或预防肿瘤的药物中的应用”是指可以抑制肿瘤的生长、发展和/或转移，主要向所需要的人或动物给治予治疗有效剂量的本发明的化合物以抑制、减慢或逆转受治疗者肿瘤的生长、发展或扩撒。
本发明的化合物是指本发明所有的通式化合物，包括通式I、通式Ia、通式Ib、通式Ic或通式Id任一通式所述的化合物及具体化合物。
具体实施方式
下面代表性的实施例是为了更好地说明本发明，而非用于限制本发明的保护范围。
实施例1  3-乙炔基-4-甲基-N-[4-((4-甲基呱嗪-1-基)甲基)-3-三氟甲基苯基]苯甲酰胺的制备
Figure PCTCN2014088911-appb-000011
步骤1  3-碘-4-甲基-N-[4-(4-甲基呱嗪-1-基)甲基)-3-三氟甲基苯基]苯甲酰胺的制备
在反应器中加入4-(4-甲基呱嗪-1-基甲基)-3-三氟甲基苯胺(2.27g，8.3mmol)、3-碘-4-甲基-苯甲酰氯(10mmol)、15ml四氢呋喃、10ml三乙胺，室温搅拌4小时。加入饱和NaHCO3溶液洗涤，乙酸乙酯和水萃取，饱和NaCl溶液洗涤，无水Na2SO4干燥，减压蒸馏除去溶剂。残留物经硅胶柱纯化，得到标题化合物，为黄色油状物。
1H NMR(500MHz,CDCl3)δ:8.39(s,1H,N-H),8.29(s,1H,Ar-H),7.88(d,1H,Ar-H),7.86(s,1H,Ar-H),7.75(d,1H,Ar-H),7.73(d,1H,Ar-H),7.28(d,1H,Ar-H),3.62(s,2H,PhCH2),2.60(b,8H,4×-CH2),2.47(s,3H,-CH3),2.31(s,3H,-CH3)。
步骤2  3-三甲基硅烷基乙炔基-4-甲基-N-[4-((4-甲基呱嗪-1-基)甲基)-3-三氟甲基苯基]苯甲酰胺的制备
将步骤1所得物(3.1g，6.1mmol)、Pd(PPh3)2Cl2(426mg，0.61mmol)、CuI(231mg，1.21mmol)置于反应器中，加入甲苯30ml作溶剂，三乙胺1ml维持 碱性环境。惰性气体保护下，向该混合物中加入三甲基硅烷基乙炔(3.0g，30.3mmol)，58℃搅拌24小时。反应结束，向反应混合物中加入乙酸乙酯和水进行萃取，合并有机层，用饱和NaCl溶液洗涤，加入无水Na2SO4干燥。减压浓缩，残留物经硅胶柱纯化，得到标题化合物，为黄色固体。
1H NMR(500MHz,CDCl3)δ:8.30(s,1H,N-H),7.86(s,1H,Ar-H),7.83(d,1H,Ar-H),7.72(s,1H,Ar-H),7.55(d,1H,Ar-H),7.41(d,1H,Ar-H),7.24(d,1H,Ar-H),3.60(s,2H,PhCH2),2.48(b,8H,4×-CH2),2.45(s,3H,-CH3),2.28(s,3H,-CH3),0.26(s,9H,3×-CH3)。
步骤3  3-乙炔基-4-甲基-N-[4-((4-甲基呱嗪-1-基)甲基)-3-三氟甲基苯基]苯甲酰胺的制备
将步骤2所得物(1.59g，3.3mmol)、碳酸钾(1.82g，13.2mmol)、20ml甲醇混合于反应器中，惰性气体保护下，室温搅拌3小时。反应结束，旋转蒸发仪上除去甲醇，加入乙酸乙酯和水进行萃取，合并有机层，用饱和NaCl溶液洗涤，加入无水Na2SO4干燥。然后将该有机溶液在旋转蒸发仪上浓缩，残留物经硅胶柱纯化，得到标题化合物，为黄色油状液体。
1H NMR(500MHz,CDCl3)δ:10.47(s,1H,N-H),8.19(s,1H,Ar-H),8.08(s,1H,Ar-H),8.04(d,1H,Ar-H),7.91(d,1H,Ar-H),7.70(d,1H,Ar-H),7.47(d,1H,Ar-H),4.50(s,1H,≡CH),3.56(s,2H,PhCH2),2.50(s,3H,-CH3),2.36(b,8H,4×CH2),2.15(s,3H,-CH3)。
实施例2  3-((1H-吡咯并[2,3-b]吡嗪-5-基)乙炔基)-4-甲基-N-[4-((4-甲基呱嗪-1-基)甲基)-3-三氟甲基苯基]苯甲酰胺的制备
Figure PCTCN2014088911-appb-000012
在10ml封管中加入实施例1制备的化合物(126mg，0.3mmol)、5-溴-1H-吡咯并[2,3-b]吡嗪(59mg，0.3mmol)、Pd(PPh3)2Cl2(63mg，0.006mmol)、CuI(18mg，0.09mmol)、1mLEt3N和5mLDMF，惰性气体保护下，80℃搅拌反应8小时。反应结束，用乙酸乙酯和水进行萃取，合并有机层，饱和NaCl溶液洗涤，无水Na2SO4干燥。减压浓缩，残留物经硅胶柱纯化，得到所述化合物，为类白色固体。
1H NMR(500MHz,CDCl3)δ:8.91(br,1H,-NH),8.46(s,1H,Ar-H),8.02(d,1H,Ar-H),7.98(s,1H,Ar-H),7.87(s,1H,Ar-H),7.85(s,-NH,1H),7.78-7.80(m,1H,Ar-H),7.69-7.70(d,1H,Ar-H),7.60-7.62(m,1H,Ar-H),7.35(d,1H,Ar-H),6.72-6.73(m,1H,Ar-H),3.61(s,2H,-CH2),2.60(s,3H,-CH3),2.54(b,8H,-CH2),2.33(s,3H,-CH3)。
ESI-MS m/z:[M+H]+＝533.1，计算值为533.2。
实施例3  3-((1H-吡咯并[2,3-b]吡嗪-5-基)乙炔基)-4-甲基-N-[4-((4-甲基呱嗪-1-基)甲基)-3-三氟甲基苯基]苯甲酰胺盐酸盐
称取3-((1H-吡咯并[2,3-b]吡嗪-5-基)乙炔基)-4-甲基-N-[4-((4-甲基呱嗪-1-基)甲基)-3-三氟甲基苯基]苯甲酰胺(30mg)溶于5mL甲醇中，滴加氯化氢乙酸乙酯溶液至pH值为3左右，室温搅拌3h，减压蒸去挥发性物质，50℃真空干燥5h，得到标题化合物。
1H NMR(300MHz,DMSO-d6)δ:12.34(s,1H),10.61(s,1H),10.25(b,1H),8.56(s,1H),8.26(s,2H),8.14(d,1H),7.96-8.01(m,2H),7.73(d,1H),7.56(d,1H),6.67-6.69(m,1H),3.70(s,2H),3.37(m,4H),2.89-3.06(m,4H),2.77(s,3H),2.61(s,3H)。
1H NMR(300MHz,DMSO-d6+D2O)δ:10.62(s,1H),8.57(s,1H),8.22(s,2H),8.07(d,1H),7.93-7.99(m,2H),7.74(d,1H),7.56(d,1H),6.71(d,1H),3.70(s,2H),3.38-3.42(m,2H),2.91-3.06(m,4H),2.81(s,3H),2.61(s,3H),2.42(m,2H)。
实施例4  3-((1H-吡唑并[3,4-b]吡嗪-5-基)乙炔基)-4-甲基-N-[4-(4-甲基呱嗪-1-基)甲基-3-三氟甲基苯基]苯甲酰胺
Figure PCTCN2014088911-appb-000013
步骤1  3-氨基-6-溴吡嗪-2-甲酸甲酯的制备
在反应器中加入3-氨基吡嗪-2-甲酸甲酯(4.59g，30mmol)、N-溴代丁二酰亚胺(5.34g，30mmol)和乙腈(100mL)，室温搅拌过夜，过滤，滤饼用乙腈洗 涤，干燥滤饼，得到标题化合物，为黄色固体。
1H-NMR(500MHz,DMSO-d6)δ:8.42(s,1H,Ar-H),7.54(s,2H,-NH2),3.86(s,3H,-CH3)。
步骤2  3,6-二溴吡嗪-2-甲酸甲酯的制备
在反应器中加入3-氨基-6-溴吡嗪-2-甲酸甲酯(4.62g，20mmol)、氢溴酸水溶液(48％，24ml)、乙酸(3.2ml)，冷却到-5℃。依次缓慢加入液溴(3.2ml，60mmol)的乙酸(5ml)溶液和亚硝酸钠(4.8g，70mmol)的水溶液(20ml)。-5℃搅拌反应1h。反应结束，用饱和亚硫酸钠溶液洗涤，加入乙酸乙酯和水萃取，饱和NaCl溶液洗涤，无水硫酸钠干燥，减压蒸馏除去溶剂。残留物经硅胶柱纯化，得到标题化合物，为类白色固体。
1H-NMR(500MHz,DMSO-d6)δ:8.92(s,1H,Ar-H),3.95(s,3H,-CH3)。
步骤3  3,6-二溴-2-羟甲基吡嗪的制备
在反应器中加入3,6-二溴吡嗪-2-甲酸甲酯(5.0g，17mmol)、四氢呋喃(100ml)，冷却到-78℃。缓慢滴加二异丁基氢化铝(34ml，34mmol)，-78℃下反应2h。反应结束，-78℃下加入冰醋酸淬灭，减压蒸馏除去溶剂。残留物溶于3N的盐酸中，加入二氯甲烷和水萃取，饱和NaCl溶液洗涤，无水Na2SO4干燥，减压蒸馏除去溶剂。残留物经硅胶柱纯化，得到标题化合物，为类白色固体。
1H-NMR(500MHz,DMSO-d6)δ:8.64(s,1H,Ar-H),5.61(t,1H,O-H),3.95(d,2H,-CH2)。
步骤4  3,6-二溴吡嗪-2-基甲醛的制备
在反应器中加入3,6-二溴-2-羟甲基吡嗪(1.7g，6.3mmol)、二氧化锰(5.5g，63mmol)，二氯甲烷(60ml)，室温搅拌30h。反应结束，过滤，热的二氯甲烷洗涤，减压蒸馏除去溶剂，得到标题化合物，为类白色固体。
1H-NMR(500MHz,DMSO-d6)δ:10.01(s,1H,-CHO),5.61(s,1H，Ar-H)。
步骤5  5-溴-1H-吡唑[3,4-b]吡嗪的制备
在反应器中加入3,6-二溴吡嗪-2-基甲醛(600mg，2.26mmol)、无水四氢呋喃(60ml)，室温搅拌下缓慢加入水合肼(1.12g，22.6mol)的四氢呋喃(5ml)溶液。加热至65℃反应6h。减压蒸馏除去溶剂，残留物经硅胶柱纯化，得到标题化合物，为淡黄色固体。
1H-NMR(300MHz,DMSO-d6)δ:14.35(s,1H,N-H),8.74(s,1H,Ar-H),8.45(s,1H,Ar-H)。
步骤6  3-((1H-吡唑[3,4-b]吡嗪-5-基)乙炔基)-4-甲基-N-(4-((4-甲基呱嗪-1-基)甲基)-3-三氟甲基苯基)苯甲酰胺的制备
Figure PCTCN2014088911-appb-000014
在反应器中加入5-溴-1H-吡唑[3,4-b]吡嗪(59.4g，0.3mmol)、3-乙炔基-4-甲基-N-(4-((4-甲基呱嗪-1-基)甲基)-3-三氟甲基苯基)苯甲酰胺(126mg，0.3mmol)、双三苯基磷二氯化钯(22mg，0.03mmol)、三环己基膦(16mg，0.06mmol)、碘化亚铜(6mg，0.03mmol)、碳酸铯(99mg，0.3mmol)和6滴N,N-二异丙基乙胺，80℃搅拌过夜。反应结束，加入乙酸乙酯和氨水萃取，饱和NaCl溶液洗涤，无水Na2SO4干燥，减压蒸馏除去溶剂。残留物经硅胶柱纯化，得到标题化合物，为棕色固体。
1H-NMR(500MHz,DMSO-d6)δ:14.36(b,1H),10.56(s,1H),8.88(s,1H,Ar-H),8.52(s,1H,Ar-H),8.28(d,1H,Ar-H),8.22(d,1H,Ar-H),8.08(d,1H,Ar-H),7.99(m,1H,Ar-H),7.71(d,1H,Ar-H),7.57(d,1H,Ar-H),3.60(s,2H,PhCH2),2.62(b,8H,4×-CH2),2.36(b,6H,2×-CH3)。
ESI-MS m/z:[M+H]+＝534.3。
实施例5  3-((7-氟-5H-吡咯并[2,3-b]吡嗪-2-基)乙炔基)-4-甲基-N-[4-(4-甲基呱嗪-1-基)甲基-3-三氟甲基苯基]苯甲酰胺
Figure PCTCN2014088911-appb-000015
步骤1  2-溴-7-氟-5H-吡咯并[2,3-b]吡嗪的制备
在干燥的100ml茄形瓶中，加入2-溴-5H-吡咯并[2,3-b]吡嗪(500mg，2.52mmol)、1-氯甲基-4-氟-1,4-二氮双环[2.2.2.]辛烷双氟硼酸盐(SelectFluor，893mg，2.52mmol)、醋酸(2mL)和乙腈(6mL)，室温搅拌2h后加热到80℃，反 应48h，冷却到室温，浓缩。加入水和乙酸乙酯萃取，浓缩，干燥，过滤，过柱纯化，得到标题化合物，为类白色固体，直接用于下一步。
步骤2  3-((7-氟-5H-吡咯并[2,3-b]吡嗪-2-基)乙炔基)-4-甲基-N-[4-(4-甲基呱嗪-1-基)甲基-3-三氟甲基苯基]苯甲酰胺的制备
使用与实施例4步骤6相同的方法，以3-乙炔基-4-甲基-N-[4-(4-甲基呱嗪-1-基甲基)-3-三氟甲基苯基]苯甲酰胺与2-溴-7-氟-5H-吡咯并[2,3-b]吡嗪为原料，制得标题化合物，为黄色固体。
1H NMR(300MHz,DMSO-d6)δ:10.56(s,1H),8.65(s,1H),8.28(s,1H),8.22(s,1H),8.07(d,1H),8.06(s,1H),7.98(d,1H),7.72(d,1H),7.57(d,1H),3.58(s,2H),2.62(s,3H),2.40(m,8H),2.17(s,3H)。
ESI-MS m/z:[M+H]+＝551.3。
实施例6  3-((7-氟-5H-吡咯并[2,3-b]吡嗪-2-基)乙炔基)-4-甲基-N-[4-(4-甲基呱嗪-1-基)甲基-3-三氟甲基苯基]苯甲酰胺盐酸盐
称取3-((7-氟-5H-吡咯并[2,3-b]吡嗪-2-基)乙炔基)-4-甲基-N-[4-(4-甲基呱嗪-1-基)甲基-3-(三氟甲基)苯基]苯甲酰胺(30mg)溶于5mL甲醇中，滴加氯化氢乙酸乙酯溶液至pH值为3左右，室温搅拌3h，减压蒸去挥发性物质，50℃真空干燥5h，得到标题化合物，为类白色固体。
1H NMR(300MHz,DMSO-d6)δ:12.27(s,1H),10.61(s,1H),10.16(b,1H),8.64(s,1H),8.28(s,1H),8.25(s,1H),8.14(d,1H),8.06(s,1H),7.98(d,1H),7.74(d,1H),7.56(d,1H),3.77(s,2H),3.39(d,4H),2.92-3.03(m,4H),2.77(s,3H),2.61(s,3H)。
1H NMR(300MHz,DMSO-d6+D2O)δ:10.60(s,1H),8.65(s,1H),8.26(s,1H),8.23(s,1H),8.11(d,1H),8.02(s,1H),7.97(d,1H),7.74(d,1H),7.56(d,1H),3.72(s,2H),3.39-3.42(m,4H),2.93-3.07(m,4H),2.80(s,3H),2.62(s,3H)。
实施例7  3-((1H-咪唑并[4,5-b]吡嗪-5-基)乙炔基)-4-甲基-N-[4-(4-甲基呱嗪-1-基)-甲基-3-(三氟甲基)苯基]苯甲酰胺
Figure PCTCN2014088911-appb-000016
步骤1  2,3-二氨基-5-溴吡嗪的制备
将2-氨基-3,5-二溴吡嗪(10g，0.04mol)加入氨水(50ml)中，加热至110℃反应16小时后，加入乙酸乙酯和H2O萃取，合并有机层，浓缩，柱分离，得标题化合物。
1H NMR(300MHz,CDCl3)δ:7.60(s,1H),4.37(b,2H),4.19(b,2H)。
步骤2  5-溴-1H-咪唑并[4,5-b]吡嗪的制备
将2,3-二氨基-5-溴吡嗪(1g，0.005mol)加入乙酸二乙氧基甲酯(5ml)中，N2保护，加热至120-130℃，反应4小时，得到棕色澄清液，加入乙酸乙酯和H2O萃取，合并有机层，浓缩，柱分离，得到标题化合物。
1H NMR(300MHz,CDCl3)δ:8.45(s,1H),8.32(s,1H)。
ESI-MS m/z:[M+H]+＝199.0。
步骤3  3-((1H-咪唑并[4,5-b]吡嗪-5-基)乙炔基)-4-甲基-N-[4-(4-甲基呱嗪-1-基)甲基-3-(三氟甲基)苯基]苯甲酰胺的制备
使用与实施例4步骤6相同的方法，以3-乙炔基-4-甲基-N-[4-(4-甲基呱嗪-1-基甲基)-3-三氟甲基苯基]苯甲酰胺和5-溴-1H-咪唑并[4,5-b]吡嗪为原料，制得目标化合物。
1H-NMR(300MHz,DMSO-d6)δ:10.59(s,1H),9.50(b,1H),8.89(s,1H),8.75(s,1H),8.22-8.27(m,2H),8.13(d,1H),7.95-7.99(m,1H),7.72(d,1H),7.57(d,1H),3.67(s,2H),3.34(b,2H),2.89-3.05(m,4H),2.80(s,3H),2.61(s,3H),2.33-2.40(m,2H)。
ESI-MS m/z:[M+H]+＝534.2。
实施例8  3-((1H-吡咯并[2,3-b]吡嗪-5-基)乙炔基)-4-甲基-N-(1-(4-甲基呱嗪-1-基)-2,3-二氢-1H-茚-5-基)苯甲酰胺
Figure PCTCN2014088911-appb-000017
步骤1  3-乙炔基-4-甲基-N-(1-氧代-2,3-二氢-1H-茚-5-基)苯甲酰胺的制备
Figure PCTCN2014088911-appb-000018
在反应器中加入3-乙炔基-4-甲基苯甲酸(5.0g，17mmol)、四氢呋喃(100mL)和2滴DMF，0℃下缓慢滴加氯化亚砜(1.9mL，26mmol)，0℃下继续反应2h。反应结束后，减压浓缩得3-乙炔基-4-甲基苯甲酰氯，将所得酰氯溶于20mL THF中，并滴加到30mL溶解有2.5g 5-氨基-1-氧代-2,3-二氢-1H-茚的四氢呋喃溶液中,滴加7mL Et3N，室温反应1h，反应结束后减压蒸除溶剂，加入乙酸乙酯和水萃取，饱和NaCl水溶液洗涤，无水Na2SO4干燥，过滤，旋干，柱层析纯化得标题化合物。
ESI-MS m/z:[M+H]+＝290.3。
步骤2  3-乙炔基-4-甲基-N-(1-(4-甲基呱嗪-1-基)-2,3-二氢-1H-茚-5-基)-苯甲酰胺
Figure PCTCN2014088911-appb-000019
在反应器中加入步骤1所得物3-乙炔基-4-甲基-N-(1-氧代-2,3-二氢-1H-茚-5-基)苯甲酰胺(2.9g，10mmol)、甲基呱嗪(1g，10mmol)、二氯乙烷(100mL)、钛酸四异丙酯(2.9g,10mmol)，室温反应12h，反应结束后，过滤，减压浓缩，加入乙酸乙酯和水萃取，饱和NaCl水溶液洗涤，无水Na2SO4干燥，过滤，旋干，柱层析纯化得标题化合物。
ESI-MS m/z:[M+H]+＝374.3。
步骤3  3-((1H-吡咯并[2,3-b]吡嗪-5-基)乙炔基)-4-甲基-N-(1-(4-甲基呱嗪-1-基)-2,3-二氢-1H-茚-5-基)苯甲酰胺的制备
在反应器中加入5-溴-1H-吡咯并[2,3-b]吡嗪(59.4g，0.3mmol)、步骤2所得物3-乙炔基-4-甲基-N-(1-(4-甲基呱嗪-1-基)-2,3-二氢-1H-茚-5-基)-苯甲酰胺(112mg,0.3mmol)、双三苯基磷二氯化钯(22mg,0.03mmol)、三环己基膦(16mg,0.06mmol)、碘化亚铜(6mg,0.03mmol)、碳酸铯(99mg,0.3mmol)、6滴N,N-二异丙基乙胺，80℃下反应12h，反应结束后，加入乙酸乙酯和氨水萃取，饱和NaCl水溶液洗涤，无水Na2SO4干燥，过滤，旋干，柱层析纯化得目标化合物。
1H NMR(500MHz,DMSO-d6)δ:12.30(s,1H,N-H),10.22(s,1H,N-H),8.55(s,1H,Ar-H),8.21(s,1H,Ar-H),7.99(s,1H,Ar-H),7.92(d,1H,Ar-H),7.70(m,1H,Ar-H),7.54(m,2H,Ar-H),7.22(d,1H,Ar-H),6.68(d,1H,Ar-H),4.23(b,1H,-CH),2.87(b,2H,-CH2),2.77(b,2H,-CH2),2.59(s,3H,-CH3),2.35(b,8H,4×-CH2),2.15(s,3H,-CH3)。
ESI-MS m/z:[M+H]+＝491.3。
实施例9  3-((3-氟-1H-吡咯并[2,3-b]吡嗪-5-基)乙炔基)-4-甲基-N-(1-(4-甲基呱嗪-1-基)-2,3-二氢-1H-茚-5-基)苯甲酰胺
Figure PCTCN2014088911-appb-000020
在反应器中加入实施例5步骤1所得物3-氟-5-溴-1H-吡咯并[2,3-b]吡嗪(65mg，0.3mmol)、实施例8步骤2所得物3-乙炔基-4-甲基-N-(1-(4-甲基呱嗪-1-基)-2,3-二氢-1H-茚-5-基)-苯甲酰胺(112mg,0.3mmol)、双三苯基磷二氯化钯(22mg,0.03mmol)、三环己基膦(16mg,0.06mmol)、碘化亚铜(6mg,0.03mmol)、碳酸铯(99mg,0.3mmol)、6滴N,N-二异丙基乙胺，80℃反应12h。反应结束后，加入乙酸乙酯和氨水萃取，饱和NaCl水溶液洗涤，无水Na2SO4干燥，过滤，浓缩，柱层析纯化得目标化合物。
1H NMR(500MHz,DMSO-d6)δ:10.22(s,1H,N-H),8.64(s,1H,Ar-H),8.23(s,1H,Ar-H),8.04(s,1H,Ar-H),7.94(d,1H,Ar-H),7.70(s,1H,Ar-H),7.54(m, 2H,Ar-H),7.22(d,1H,Ar-H),4.24(t,1H,-CH),2.89(m,2H,-CH2),2.77(b,2H,-CH2),2.60(s,3H,-CH3),2.37(b,8H,4×-CH2),2.17(s,3H,-CH3)。ESI-MS m/z:[M+H]+＝509.2。
实施例10  3-((1H-吡咯并[2,3-b]吡嗪-5-基)乙炔基)-4-甲基-N-(4-((3-甲基-3,8-二氮杂双环[3.2.1]辛烷-8-基)甲基)-3-(三氟甲基)苯基)苯甲酰胺
Figure PCTCN2014088911-appb-000021
步骤1  1-溴甲基-2-三氟甲基-4-硝基苯的制备
Figure PCTCN2014088911-appb-000022
在反应器中加入2-三氟甲基-4-硝基甲苯(10g，50mmol)、NBS(8.9g,50mmol)、四氯化碳(50mL)、偶氮二异丁腈(AIBN，164mg，1mmol)，回流反应12h。反应结束后，过滤，滤液直接用于下一步反应。
步骤2  1-((3-叔丁氧基羰基-3,8-二氮杂双环[3.2.1]辛烷-8-基)甲基)-2-三氟甲基-4-硝基苯的制备
Figure PCTCN2014088911-appb-000023
将3-叔丁基氧基羰基-3,8-二氮杂双环[3.2.1]辛烷(10.6g，50mmol)、三乙胺(14mL，100mmol)加入到步骤1的反应滤液中，室温反应2h。反应结束后，减压蒸除溶剂，加入乙酸乙酯和水萃取，饱和NaCl水溶液洗涤，无水Na2SO4干燥，过滤，浓缩，柱层析纯化得标题化合物。
ESI-MS m/z:[M+H]+＝416.2。
步骤3  1-((3-叔丁氧羰基-3,8-二氮杂双环[3.2.1]辛烷-8-基)甲基)-2-三氟甲基-4-胺基苯的制备
Figure PCTCN2014088911-appb-000024
在反应器中加入步骤2所得物1-((3-叔丁氧羰基-3,8-二氮杂双环[3.2.1] 辛烷-8-基)甲基)-2-三氟甲基-4-硝基苯(8g，19.2mmol)、氯化胺(10g，190mmol)，铁粉(2g)、乙醇(50mL)，回流反应2h。反应结束后，过滤，减压蒸除溶剂，加入乙酸乙酯和水萃取，饱和NaCl水溶液洗涤，无水Na2SO4干燥，过滤，旋干，柱层析纯化得标题化合物。
ESI-MS m/z:[M+H]+＝386.2。
步骤4  3-乙炔基-4-甲基-N-(4-((3-叔丁氧羰基-3,8-二氮杂双环[3.2.1]辛烷-8-基)甲基)-3-(三氟甲基)苯基)苯甲酰胺的制备
Figure PCTCN2014088911-appb-000025
在反应器中加入3-乙炔基-4-甲基苯甲酸(5.0g，17mmol)、四氢呋喃(100mL)和2滴DMF，0℃下缓慢滴加氯化亚砜(1.9mL，26mmol)，0℃下继续反应2h。反应结束后，减压浓缩得酰氯物，将所得酰氯物溶于20mL THF中，并滴加到30mL溶有6.5g步骤3所得物1-((3-叔丁氧羰基-3,8-二氮杂双环[3.2.1]辛烷-8-基)甲基)-2-三氟甲基-4-胺基苯的四氢呋喃溶液中,滴加Et3N(7mL,51mol)，室温反应1h，反应结束后，减压蒸除溶剂，加入乙酸乙酯和水萃取，饱和NaCl水溶液洗涤，无水Na2SO4干燥，过滤，浓缩，柱层析纯化得标题化合物。
ESI-MS m/z:[M+H]+＝528.3。
步骤5  3-乙炔基-4-甲基-N-(4-((3-甲基-3,8-二氮杂双环[3.2.1]辛烷-8-基)甲基)-3-(三氟甲基)苯基)苯甲酰胺
Figure PCTCN2014088911-appb-000026
在反应器中加入步骤4所得物3-乙炔基-4-甲基-N-(4-((3-叔丁氧羰基-3,8-二氮杂双环[3.2.1]辛烷-8-基)甲基)-3-(三氟甲基)苯基)苯甲酰胺(5g,9.4mmol)、40％甲醛水溶液(10mL)、甲酸(50mL)，回流反应3h。反应结束后，加入乙酸乙酯和水萃取，饱和NaCl水溶液洗涤，无水Na2SO4干燥，过滤，旋干，柱层析纯化得标题化合物。
ESI-MS m/z:[M+H]+＝442.3。
步骤6  3-((1H-吡咯并[2,3-b]吡嗪-5-基)乙炔基)-4-甲基-N-(4-((3-甲基-3,8-二氮杂双环[3.2.1]辛烷-8-基)甲基)-3-(三氟甲基)苯基)苯甲酰胺
Figure PCTCN2014088911-appb-000027
在反应器中加入5-溴-1H-吡咯并[2,3-b]吡嗪(59.4mg，0.3mmol)、步骤5所得物3-乙炔基-4-甲基-N-(4-((3-甲基-3,8-二氮杂双环[3.2.1]辛烷-8-基)甲基)-3-(三氟甲基)-苯基)苯甲酰胺(112mg,0.3mmol)、双三苯基磷二氯化钯(22mg,0.03mmol)、三环己基膦(16mg,0.06mmol)、碘化亚铜(6mg,0.03mmol)、碳酸铯(99mg,0.3mmol)、6滴N,N-二异丙基乙胺，80℃反应12h。反应结束后，加入乙酸乙酯和氨水萃取，饱和NaCl水溶液洗涤，无水Na2SO4干燥，过滤，旋干，柱层析纯化得目标化合物。
1H NMR(500MHz,DMSO-d6)δ:12.31(s,1H,N-H),10.54(s,1H,N-H),8.55(s,1H,Ar-H),8.24(b,1H,Ar-H),8.20(b,1H,Ar-H),8.06(d,1H,Ar-H)7.99(d,1H,Ar-H),7.95(d,1H,Ar-H),7.67(d,1H,Ar-H),7.55(d,1H,Ar-H),7.68(d,H,Ar-H),3.52(s,2H,PhCH2),2.98(b,2H,2×-CH),2.61(s,3H,-CH3),2.46(b,2H,-CH2),2.25(b,2H,-CH2),2.15(s,3H,-CH3),1.82(b,2H,-CH2),1.70(b,2H,-CH2)。
ESI-MS m/z:[M+H]+＝559.3。
实施例11  3-((3-氟-1H-吡咯并[2,3-b]吡嗪-5-基)乙炔基)-4-甲基-N-(4-((3-甲基-3,8-二氮杂双环[3.2.1]辛烷-8-基)甲基)-3-(三氟甲基)苯基)苯甲酰胺
Figure PCTCN2014088911-appb-000028
在反应器中加入5-溴-3-氟-1H-吡咯并[2,3-b]吡嗪(65mg，0.3mmol)、实施例10步骤5所得物3-乙炔基-4-甲基-N-(4-((3-甲基-3,8-二氮杂双环[3.2.1]辛烷-8-基)甲基)-3-(三氟甲基)苯基)苯甲酰胺(112mg，0.3mmol)、双三苯基磷 二氯化钯(22mg，0.03mmol)、三环己基膦(16mg，0.06mmol)、碘化亚铜(6mg，0.03mmol)、碳酸铯(99mg，0.3mmol)、6滴N,N-二异丙基乙胺，80℃反应12h。反应结束后，加入乙酸乙酯和氨水萃取，饱和NaCl水溶液洗涤，无水Na2SO4干燥，过滤，旋干，柱层析纯化得目标化合物。
1H NMR(500MHz,DMSO-d6)δ:10.54(s,1H,N-H),8.64(s,1H,Ar-H),8.27(b,1H,Ar-H),8.20(b,1H,Ar-H),8.07(b,1H,Ar-H),8.05(b,1H,Ar-H),7.96(m,1H,Ar-H),7.67(d,1H,Ar-H),7.55(d,1H,Ar-H),3.52(s,2H,PhCH2),2.98(b,2H,2×-CH),2.61(s,3H,-CH3),2.46(b,2H,-CH2),2.25(b,2H,-CH2),2.15(s,3H,-CH3),1.82(b,2H,-CH2),1.70(b,2H,-CH2)。
ESI-MS m/z:[M+H]+＝577.3。
实验例1  本发明的化合物体外细胞活性评价
本实验测试本发明的化合物对白血病细胞的抑制活性，使用伊马替尼和Ponatinib作为对照。伊马替尼参照中国专利CN1043531C中描述的方法制得并通过氢谱和质谱鉴定，Ponatinib购自上海辛阔化学科技有限公司，Ponatinib盐酸盐参照本发明实施例3的方法制备并通过氢谱和质谱鉴定。
1.实验材料
1.1化合物
使用以上代表性的实施例2、4、5、8、9、10的化合物以及伊马替尼和Ponatinib。各化合物用DMSO溶解至10mM后，用完全培养基稀释至50μM，然后用含0.1％DMSO的完全培养基稀释至10μM后，依次10倍稀释，共10个浓度。
1.2细胞
K562白血病细胞：购自美国ATCC公司
伊马替尼耐受的K562白血病细胞：购自美国ATCC公司
1.3试剂
二甲基亚砜(Dimethyl sulfoxide，DMSO)，购于美国Sigma公司；
发光法细胞活力检测试剂盒(CellTiter-
Figure PCTCN2014088911-appb-000029
Luminescent Cell Viability Assay Kit)，购于美国Promega公司；
IMEM培养基(IMEM medium)，购于美国Gibco公司；
青霉素/链霉素(Pen/Strep)，购于美国Gibco公司；
胎牛血清(Fatal bovine serun，FBS)，购于美国Gibco公司；
0.25％含EDTA胰酶(0.25％Trypsin-EDTA)，购于美国Gibco公司；
10cm细胞培养皿(10cm cell culture dish)，购于美国Corning公司；
50mL离心管(50mL centrifuge tube)，购于美国Corning公司；
384孔平底透光白板(384Well Flat Clear Bottom White)，购于美国Corning公司；
磷酸盐缓冲液(Phosphate Buffered Saline，PBS)，每周配制。
1.4仪器
自动聚焦荧光多功能酶标仪(PHERAstar Plus)，购于德国BMG Labtech公司。
2.实验方法：
1)收集对数期细胞，调整细胞悬液浓度至1×105个/ml，384孔板每孔加入40μL细胞悬液，每孔细胞数为4×103个/孔，边缘孔用无菌PBS填充；
2)加入10μL的以上浓度梯度的本发明的化合物。每个化合物每个浓度重复三次。空白对照加入10μL同等浓度的DMSO；
3)细胞在37℃/5％CO2培养箱中孵育；
4)加药72h后加入30μL发光法细胞活力检测试剂混合液；
5)37℃/5％CO2培养箱中孵育10min；低转速离心后在PHERAstar酶标仪上测定化学发光值；
6)细胞活力(Cell Viability)＝(RLU样品/RLU阴性)×100％，其中RLU样品为加药孔RLU(相对光单位)值，RLU阴性为不加药孔RLU值(即同等浓度DMSO处理的细胞对照)，采用Graphpad Prism 4.0数据处理软件四参数逻辑拟合模块进行处理数据计算IC50。IC50值表示与未加化合物处理组相比，化合物抑制50％细胞生长对应的化合物浓度。IC50结果见表1。
表1
Figure PCTCN2014088911-appb-000030
Figure PCTCN2014088911-appb-000031
“-”表示未检测。
从以上实验结果可以看出，本发明的化合物对白血病细胞的IC50值在nM水平，具有强的抑制活性。对于不耐药的K562白血病细胞，本发明的化合物与Ponatinib活性相当，远优于伊马替尼。而对于伊马替尼耐受的K562白血病细胞，本发明的化合物则比Ponatinib表现出更好的抑制活性。
实验例2  ABL1(T315I)酪氨酸激酶活性评价
本实验测试本发明实施例制备的化合物对ABL(T315I)激酶活性的抑制，使用伊马替尼作为对照。伊马替尼参照中国专利CN1043531C中描述的方法制得并通过氢谱和质谱鉴定。
使用商购的人源ABL T315I突变酶(Human ABL1(T315I)，active，目录号#14-522，Millipore公司，美国)测试ABL(T315I)酪氨酸激酶活性。按厂商说明书进行激酶活性测定。肽底物(Peptide substrate)为Abltide(EAIYAAPFAKKK)，购于美国Millipore公司。离子交换层析滤纸P81(ion exchange filter paper)购于英国Whatman公司。[γ-33P]ATP购于Perkin Elmer公司。
本发明的化合物以及伊马替尼从1μM开始分别3倍连续稀释，共10个浓度(50.8pM，152.0pM，457.0pM，1.37nM，4.12nM，12.3nM，37.0nM，111.0nM，333.0nM和1.0μM)。每孔加入5.0μM Abltide，然后加入人源T315I突变酶。室温下加入[γ-33P]ATP，终浓度为1.0μM，反应120分钟。将20μl等分试样转移到P81离子交换层析纸上。然后层析纸用0.75％磷酸溶液充分洗涤3次，再用丙酮洗涤一次。最后，进行γ-33P放射性测定。实验结果见表2。
表2
Figure PCTCN2014088911-appb-000032
以上实验结果表明，本发明的化合物对T315I突变酶的IC50显著优于伊马替尼，具有强效的抑制T315I突变酶的能力。
从本发明的实验结果可以得出，本发明的化合物不仅对没有突变的白血病细胞具有非常好的效果，而且能够显著抑制T315I突变酶，因此是广谱的BCR-ABL抑制剂。对于对酪氨酸激酶抑制剂(TKI)治疗耐药或抵抗的肿瘤病患者，例如慢性粒细胞白血病(CML)慢性期、急变期、加速期患者以及费城染色体阳性(Ph+)的慢性粒细胞白血病和急性淋巴细胞白血病患者应具有好的前景。
实验例3  药物代谢实验
1 实验材料
1.1 化合物
使用以上代表性的实施例3和6制备的本发明的化合物。其中，口服药物配方为生理盐水溶解，制成3mg/ml混悬液；尾静脉注射药物配方为体积比DMSO:聚氧乙烯蓖麻油:生理盐水＝1:30:69的混合溶液，制成2.5mg/ml溶液。
1.2 动物
雄性SD大鼠，每组各3只，体重150g-250g，上海西普尔-必凯实验动物有限公司提供。受试大鼠实验前给予2～4天的环境适应期，给药前禁食8-12h，给药2h后给水，4h后给食。
1.3 试剂
甲醇(色谱纯)：Spectrum公司生产；
乙腈(色谱纯)：Spectrum公司生产；
其余试剂均为市售分析纯。
1.4 仪器
美国AB公司API 4000型三重四级杆液质联用仪，配有电喷雾离子源(ESI)，LC-20AD双泵；SIL-20AC自动进样器；CTO-20AC柱温箱；DGU-20A3R脱气机；Analyst QS A01.01色谱工作站；Milli-Q超纯水器(Millipore Inc)；Qilinbeier Vortex-5振荡器；HITACHI CF16RⅩⅡ台式高速冷冻离心机。
2 实验方法
1)SD大鼠禁食但可自由饮水12小时后，采取0时刻空白血浆；
2)取步骤1)中的大鼠3只，灌胃(Intragastric administration,I.G.)给予实施例3化合物15mg/kg；
取步骤1)中的大鼠3只，尾静脉(Intravenous administration，I.V.)给予实施例3化合物3mg/kg；
取步骤1)中的大鼠3只，灌胃给予实施例6化合物15mg/kg；
取步骤1)中的大鼠3只，尾静脉(Intravenous administration，I.V.)给予实施例6化合物5mg/kg；
3)于灌胃后10min、30min、1h、2h、4h、6h、8h、10h、24h眼底静脉丛连续取血于分布有肝素的EP管中，8000rpm/min离心5min后取上层血浆，-20℃冻存，待LC-MS/MS分析；
4)根据步骤3)所得的血药浓度-时间数据，采用WinNonlin软件求算药代动力学参数，见表3。
5)于尾静脉注射给药后5min、15min、30min、1h、2h、4h、8h、24h眼底静脉丛连续取血于分布有肝素的EP管中，8000rpm/min离心5min后取上层血浆，-20℃冻存，待LC-MS/MS分析。
6)根据步骤5)所得的血药浓度-时间数据，用WinNonlin软件求算药代动力学参数，见表3。
表3 药代动力学参数
Figure PCTCN2014088911-appb-000033
Wei-Sheng Huang等(Discovery of3-[2-(Imidazo[1,2-b]pyridazin-3-yl)ethynyl]-4-methyl-N-{4-[(4-methyl-piperazin-1-yl)-methyl]-3-(trifluoromethyl)phenyl}benzamide(AP24534),a Potent,Orally Active Pan-Inhibitorof Breakpoint Cluster Region-Abelson(BCR-ABL)Kinase Including the T315I Gatekeeper Mutant，J.Med.Chem.2010(53)4701–4719)报导，口服给予Ponatinib 15mg/kg，峰浓度(Cmax)为204.8ng/ml，口服生物利用度(F)为18.2％。由此可见，本发明的化合物的Cmax高于Ponatinib，具有较高的口服生物利用度。
实验例4 亚急毒实验
1 实验材料
1.1 化合物
使用以上实施例6制备的本发明的化合物，以Ponatinib盐酸盐为对照，口服药物配方为：生理盐水溶解。
1.2 动物
雄性小鼠，24只，体重18±2g，购自南京市江宁区青龙山动物繁殖场。受试小鼠实验前给予2～4天的环境适应期，给药前禁食8-12h，给药2h后给水，4h后给食。
1.3 试剂
超纯水:Milli-Q超纯水器(Millipore Inc)仪器自制；
1.4 仪器
Milli-Q超纯水器(Millipore Inc)；LT501电子天平。
2 实验方法
1)将18只小鼠随机分为3组，分别为空白对照组，Ponatinib盐酸盐药物组，实施例6药物组，每组6只；
2)小鼠灌胃给药，给药方式为：第0-2天，给药剂量10mg/kg；第3-5天，给药剂量20mg/kg；第6-9天，给药剂量为40mg/kg；
3)记录小鼠体重，计算平均体重和相对体重变化(RCBW％)，通过相对体重变化反映动物体重受药物影响的情况，结果见表4和表5。计算公式：RCBW％＝(给药某一天的体重-给药第一天的体重)/给药第一天的体重×100％。
表4 平均体重表(g)
Figure PCTCN2014088911-appb-000034
表5 相对体重变化表(RCBW％)
Figure PCTCN2014088911-appb-000035
*表示与空白对照组相比p<0.05。
以上亚急毒实验结果表明，与空白对照组相比，Ponatinib组对小鼠体重有显著影响，P值<0.05，而本发明的化合物对小鼠体重没有影响，表现出极低的毒性。因而，本发明的药物在毒副作用方面明显优于Ponatinib。
尽管以上已经对本发明作了详细描述，但是本领域技术人员理解，在不偏离本发明的精神和范围的前提下可以对本发明进行各种修改和改变。本发明的权利范围并不限于上文所作的详细描述，而应归属于权利要求书。

Claims (10)

  1. 通式I的化合物或其药学可接受的盐、异构体、溶剂合物、结晶或前药，
    Figure PCTCN2014088911-appb-100001
    其中：
    X选自N和C(R5)，其中R5选自氢、卤素、C1-6烷基、卤代C1-6烷基；
    Y选自N和C(R6)，其中R6选自氢、卤素、C1-6烷基、卤代C1-6烷基；
    R1选自氢、烷基、烷氧基、卤代烷基、卤代烷氧基、-OH、-NH2、卤素和CN；
    R2选自氢、烷基、烷氧基、卤代烷基、卤代烷氧基、-OH、-NH2、卤素和CN；
    W选自C1-6亚烷基、-C(O)-，与R4形成4-8元环烷基或不存在；
    R3选自取代或未取代的五元、六元、七元和八元含氮杂环基；
    R4选自氢、烷基、卤代烷基、或与W一起形成4-8元环烷基；
    其条件是排除以下化合物：
    3-((1H-吡咯并[2,3-b]吡嗪-5-基)乙炔基)-4-甲基-N-[4-((4-甲基呱嗪-1-基)甲基)-3-三氟甲基苯基]苯甲酰胺。
  2. 根据权利要求1的化合物或其药学可接受的盐、异构体、溶剂合物、结晶或前药，其中所述化合物为通式Ia所示的化合物，
    Figure PCTCN2014088911-appb-100002
    其中：
    X选自N和C(R5)，其中R5选自氢、卤素、C1-6烷基、卤代C1-6烷基；
    Y选自N和C(R6)，其中R6选自氢、卤素、C1-6烷基、卤代C1-6烷基；
    R1选自氢、烷基、烷氧基、卤代烷基、卤代烷氧基、-OH、-NH2、卤素和CN；
    R2选自氢、烷基、烷氧基、卤代烷基、卤代烷氧基、-OH、-NH2、卤素和CN；
    R3选自取代或未取代的五元、六元、七元和八元含氮杂环基；
    W选自C1-6亚烷基、-C(O)-或不存在；
    R4选自氢、C1-6烷基、卤代C1-6烷基；
    其条件是排除以下化合物：
    3-((1H-吡咯并[2,3-b]吡嗪-5-基)乙炔基)-4-甲基-N-[4-((4-甲基呱嗪-1-基)甲基)-3-三氟甲基苯基]苯甲酰胺。
  3. 根据权利要求1的化合物或其药学可接受的盐、异构体、溶剂合物、结晶或前药，其中所述化合物为通式Ib所示的化合物，
    Figure PCTCN2014088911-appb-100003
    其中：
    X选自N和C(R5)，其中R5选自氢、卤素、C1-6烷基、卤代C1-6烷基；
    Y选自N和C(R6)，其中R6选自氢、卤素、C1-6烷基、卤代C1-6烷基；
    R1选自氢、烷基、烷氧基、卤代烷基、卤代烷氧基、-OH、-NH2、卤素和CN；
    R2选自氢、烷基、烷氧基、卤代烷基、卤代烷氧基、-OH、-NH2、卤素和CN；
    R3选自取代或未取代的五元、六元、七元和八元含氮杂环基；
    W选自C1-6亚烷基、-C(O)-或不存在；
    R4选自氢、C1-6烷基、卤代C1-6烷基。
  4. 根据权利要求1的化合物或其药学可接受的盐、异构体、溶剂合物、结晶或前药，其中所述化合物为通式Ic所示的化合物，
    Figure PCTCN2014088911-appb-100004
    其中：
    X选自N和C(R5)，其中R5选自氢、卤素、C1-6烷基、卤代C1-6烷基；
    Y选自N和C(R6)，其中R6选自氢、卤素、C1-6烷基、卤代C1-6烷基；
    R1选自氢、烷基、烷氧基、卤代烷基、卤代烷氧基、-OH、-NH2、卤素和CN；
    R2选自氢、烷基、烷氧基、卤代烷基、卤代烷氧基、-OH、-NH2、卤素和CN；
    R3选自取代或未取代的五元、六元、七元和八元含氮杂环基。
  5. 根据权利要求1的化合物或其药学可接受的盐、异构体、溶剂合物、结晶或前药，其中所述化合物为通式Id所示的化合物，
    Figure PCTCN2014088911-appb-100005
    其中：
    X选自N和C(R5)，其中R5选自氢、卤素、C1-6烷基、卤代C1-6烷基；
    Y选自N和C(R6)，其中R6选自氢、卤素、C1-6烷基、卤代C1-6烷基；
    R1选自氢、烷基、烷氧基、卤代烷基、卤代烷氧基、-OH、-NH2、卤素和CN；
    R2选自氢、烷基、烷氧基、卤代烷基、卤代烷氧基、-OH、-NH2、卤素和CN；
    R3选自取代或未取代的五元、六元、七元和八元含氮杂环基。
  6. 根据权利要求1至5之任一项所述的化合物或其药学可接受的盐、异构体、溶剂合物、结晶或前药，其中
    R1选自氢、烷基、烷氧基、卤代烷基、卤素和CN，优选自氢、甲基、三氟甲基、甲氧基、乙氧基、丙氧基或异丙氧基；
    R2选自氢、烷基、卤代烷基、卤素和CN，优选自氢、甲基、乙基、丙基和 异丙基。
  7. 根据权利要求1至5之任一项所述的化合物或其药学可接受的盐、异构体、溶剂合物、结晶或前药，其中
    W选自C1-3亚烷基、-C(O)-、与R4一起构成环戊烷基或不存在；
    R3选自呱嗪基、呱啶-4-基、3,8-二氮杂双环[3.2.1]辛烷基，所述的呱嗪基、呱啶-4-基、3,8-二氮杂双环[3.2.1]辛烷基可以被一个或多个烷基、烷氧基取代，优选地R3选自4-甲基呱嗪-1-基、呱啶-4-基、1-甲基呱啶-4-基、3,8-二氮杂双环[3.2.1]辛烷-8-基、1-甲基-3,8-二氮杂双环[3.2.1]辛烷-8-基；
    R4选自甲基、三氟甲基、或与W一起构成环戊烷基；
    R5选自氢、卤素，优选选自氢、氟；
    R6选自氢、卤素，优选选自氢、氟。
  8. 根据权利要求1至7之任一项所述的化合物或其药学可接受的盐、异构体、溶剂合物、结晶或前药，其中所述化合物为选自以下的化合物：
    Figure PCTCN2014088911-appb-100006
    Figure PCTCN2014088911-appb-100007
  9. 一种药物组合物，其包含权利要求1至8之任一项所述的化合物或其药学可接受的盐、异构体、溶剂合物、结晶或前药和可药用载体。
  10. 权利要求1-8之任一项所述的化合物或其药学可接受的盐、异构体、溶剂合物、结晶或前药或权利要求9所述的药物组合物在制备用于治疗或预防肿瘤的药物中的应用。
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